Single-dose, ready-to-use injectable formulations

ABSTRACT

Provided are single-dose, ready-to-use formulations and methods for preparing the formulations that include a compound of Formula (I) 
                         
including pharmaceutically acceptable salts and amorphous and polymorph forms thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/939,713, filed onJul. 27, 2020, which claims the benefit of U.S. Ser. No. 15/806,321,filed on Nov. 7, 2017, which claims the benefit of U.S. ProvisionalApplication No. 62/418,688, filed Nov. 7, 2016, each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

Provided herein are single-dose, ready-to-use formulations that containa compound of Formula (I), including pharmaceutically acceptable salts,polymorphs and amorphous forms thereof. Further provided herein areprocesses for preparing the same.

BACKGROUND

The compound of Formula (I)

N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide,is a Wnt inhibitor. The compound of Formula (I) can be prepared asdisclosed in U.S. Pat. No. 8,252,812, incorporated by reference hereinin its entirety. The compound of Formula (I), including pharmaceuticallyacceptable salts and polymorph and amorphous forms thereof can be usedin the treatment of disorders characterized by the activation of Wntpathway signaling (e.g., cancer, abnormal cellular proliferation,angiogenesis, Alzheimer's disease, lung disease and osteoarthritis), themodulation of cellular events mediated by Wnt pathway signaling, as wellas genetic diseases and neurological conditions/disorders/diseases dueto mutations or dysregulation of the Wnt pathway and/or of one or moreof Wnt signaling components. There exists a need for formulationscontaining a compound of Formula (I), including pharmaceuticallyacceptable salts and polymorph and amorphous forms thereof, such as aready-to-use, single-dose formulation.

SUMMARY

Provided herein is a process for preparing a single-dose, ready-to-useformulation comprising a compound of Formula (I)

or a pharmaceutically acceptable salt or amorphous or polymorph formthereof, the process comprising:

(a) providing an aqueous solution comprising water;

(b) providing a slurry comprising a compound of Formula (I), or apharmaceutically acceptable salt or amorphous or polymorph form thereof;

(c) mixing the aqueous solution and the slurry to form a suspension; and

(d) filling a container with the suspension to prepare a single-dose,ready-to-use formulation.

The process provided herein comprises providing an aqueous solutioncomprising water. In some embodiments of the process provided herein,the aqueous solution comprises a buffer. In some embodiments, theaqueous buffer is a phosphate buffer. In some embodiments, the phosphatebuffer is selected from the group consisting of sodium phosphatedibasic, sodium phosphate monobasic, potassium phosphate monobasic,potassium phosphate dibasic, and mixtures thereof. In some embodiments,the phosphate buffer is a mixture of sodium phosphate dibasicheptahydrate and sodium phosphate monobasic monohydrate. In someembodiments, the buffer is phosphate buffered saline.

In some embodiments of the process provided herein, the aqueous solutioncomprises an excipient. In some embodiments, the excipient comprises asurfactant, a viscosity enhancer, or a mixture thereof. In someembodiments, the viscosity enhancer is a water-soluble polymer. In someembodiments, the viscosity enhancer is a cellulose derivative. In someembodiments, the cellulose derivative is sodium carboxymethylcellulose.In some embodiments, the aqueous solution comprises about 0.01 g/kg toabout 50 g/kg; about 0.5 g/kg to about 50 g/kg; about 1.0 g/kg to about50 g/kg; about 1 g/kg to about 25 g/kg; about 1 g/kg to about 10 g/kg;about 1 g/kg to about 7.5 g/kg; about 1 g/kg to about 5.5 g/kg; about 1g/kg to about 2.5 g/kg; about 2.5 g/kg to about 50 g/kg; about 5 g/kg toabout 50 g/kg; about 10 g/kg to about 50 g/kg; about 25 g/kg to about 50g/kg; about. 0.1 to about 5 g/kg; about 2.5 g/kg to about 7.5 g/kg;about 5 g/kg to about 10 g/kg; or about 10 g/kg to about 20 g/kg of aviscosity enhancer. In some embodiments, the aqueous solution comprisesabout 5.5 g/kg of a cellulose derivative.

In some embodiments of the process provided herein, the surfactant is apolysorbate. In some embodiments, the aqueous solution comprises about0.01 g/kg to about 5 g/kg; about 0.01 g/kg to about 2.5 g/kg; about 0.01g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75 g/kg; about 0.01g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25 g/kg; about 0.025g/kg to about 5 g/kg; about 0.05 g/kg to about 5 g/kg; about 1 g/kg toabout 5 g/kg; about 0.1 g/kg to about 5 g/kg; 0.1 g/kg to about 2.5g/kg; about 0.1 g/kg to about 1 g/kg; about 0.1 g/kg to about 0.75 g/kg;about 0.1 g/kg to about 0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg;about 0.25 g/kg to about 5 g/kg; about 0.25 g/kg to about 2.5 g/kg;about 0.25 g/kg to about 0.75 g/kg; about 0.5 g/kg to about 2.5 g/kg;about 0.5 g/kg to about 1 g/kg; or about 1 g/kg to about 2 g/kg of asurfactant. In some embodiments, the aqueous solution comprises about0.5 g/kg of a surfactant. In some embodiments, the aqueous solutioncomprises about 5.55 g/kg of sodium carboxymethylcellulose and about 0.5g/kg of polysorbate 80.

The process provided herein comprises providing a slurry comprising acompound of Formula (I), or a pharmaceutically acceptable salt oramorphous or polymorph form thereof. In some embodiments of the processprovided herein, the slurry comprises about 0.001 g/kg to about 5 g/kg;about 0.001 g/kg to about 2.5 g/kg; about 0.001 g/kg to about 1 g/kg;about 0.001 g/kg to about 0.75 g/kg; about 0.001 g/kg to about 0.5 g/kg;about 0.001 g/kg to about 0.25 g/kg; about 0.001 g/kg to about 0.01g/kg; about 0.01 g/kg to about 5 g/kg; about 0.01 g/kg to about 2.5g/kg; about 0.01 g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75g/kg; about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25g/kg; about 0.1 g/kg to about 2.5 g/kg; about 0.1 g/kg to about 1 g/kg;about 0.1 g/kg to about 0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg;about 0.1 g/kg to about 0.25 g/kg; about 0.25 g/kg to about 5 g/kg;about 0.5 g/kg to about 5 g/kg; about 1 g/kg to about 5 g/kg; about 2.5g/kg to about 5 g/kg; about 0.25 g/kg to about 0.75 g/kg; about 0.5 g/kgto about 1 g/kg; or about 1 g/kg to about 2 g/kg of the compound ofFormula (I), or a salt or amorphous or polymorph form thereof. In someembodiments, the slurry comprises about 0.15 g/kg, about 0.35 g/kg, orabout 1.15 g/kg of the compound of Formula (I), or a salt or amorphousor polymorph form thereof. In some embodiments, the compound of Formula(I) comprises a polymorph form. In some embodiments, the polymorph isForm 1 and has an X-ray powder diffraction pattern comprising peaks at °2θ values of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, thecompound of Formula (I) comprises a mixture of a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water.

In some embodiments of the process provided herein, the slurry comprisesan excipient. In some embodiments, the excipient comprises a surfactant.In some embodiments, the surfactant is a polysorbate. In someembodiments, the slurry comprises about 0.01 g/kg to about 5 g/kg; 0.01g/kg to about 2.5 g/kg; about 0.01 g/kg to about 1 g/kg; about 0.01 g/kgto about 0.75 g/kg; about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kgto about 0.25 g/kg; about 0.025 g/kg to about 5 g/kg; about 0.05 g/kg toabout 5 g/kg; about 1 g/kg to about 5 g/kg; about 0.1 g/kg to about 5g/kg; 0.1 g/kg to about 2.5 g/kg; about 0.1 g/kg to about 1 g/kg; about0.1 g/kg to about 0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg; about 0.1g/kg to about 0.25 g/kg; about 0.25 g/kg to about 5 g/kg; about 0.25g/kg to about 2.5 g/kg; about 0.25 g/kg to about 0.75 g/kg; about 0.5g/kg to about 5 g/kg; about 0.5 g/kg to about 2.5 g/kg; about 0.5 g/kgto about 1 g/kg; about 1 g/kg to about 5 g/kg; about 2.5 g/kg to about 5g/kg; or about 1 g/kg to about 2 g/kg of a surfactant. In someembodiments, the slurry comprises about 0.5 g/kg of a surfactant.

In some embodiments of the process provided herein, the slurry comprisesabout 0.15 g/kg of polymorph Form 1 or a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water and about 0.5 g/kg of polysorbate 80. In some embodiments,the slurry comprises no more than 5% by weight of other Forms. Forexample, not more than 1% or less than 0.1% of another Form, includingamorphous. In some embodiments, the slurry comprises about 0.35 g/kg ofpolymorph Form 1 or a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water and about 0.5g/kg of polysorbate 80. In some embodiments, the slurry comprises about1.15 g/kg of polymorph Form 1 or a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water andabout 0.5 g/kg of polysorbate 80.

In some embodiments of the process provided herein, the aqueous solutionis a filtered mixture. In some embodiments, the filtered mixturecomprises water. In some embodiments, the filtered mixture compriseswater and an excipient. In some embodiments, the excipient comprises asurfactant, a viscosity enhancer, or a mixture thereof. In someembodiments, the aqueous solution is a sterile filtered mixture. In someembodiments, the aqueous solution is a heat-sterilized mixture.

In some embodiments of the process provided herein, the aqueous solutioncomprises a sterile diluent.

In some embodiments of the process provided herein, the aqueous solutionis a first sterilized mixture; the slurry is a second sterilizedmixture; and the process comprises mixing the first sterilized mixtureand the second sterilized mixture.

Provided herein is a process comprising mixing the aqueous solution andthe slurry to form a suspension. In some embodiments of the processprovided herein, the aqueous solution and slurry are mixed to form asuspension comprising about 0.005 mg/mL to about 2.5 mg/mL, about 0.01mg/mL to about 2.0 mg/mL, about 0.01 mg/mL to about 1 mg/mL, about 0.01mg/mL to about 0.5 mg/mL, about 0.01 mg/mL to about 0.2 mg/mL, or about0.015 mg/mL to about 0.115 mg/mL of the compound of Formula (I) or asalt or amorphous or polymorph form thereof.

Provided herein is a process comprising filling a container with thesuspension to prepare a single-dose, ready-to-use formulation. In someembodiments of the process provided herein, the container comprises asuspension comprising about 0.005 mg/mL to about 2.5 mg/mL, about 0.005mg/mL to about 2 mg/mL, about 0.001 mg/mL to about 2 mg/mL, about 0.01mg/mL to about 1.8 mg/mL, about 0.015 mg/mL to about 0.115, about 0.025mg/mL to about 1.6 mg/mL, about 0.05 mg/mL to about 1.5 mg/mL, about0.075 mg/mL to about 1.25 mg/mL, about 0.1 mg/mL to about 1 mg/mL, orabout 0.25 mg/mL to about 0.75 mg/mL of the compound of Formula (I) or asalt or amorphous or polymorph form thereof. In some embodiments, thecontainer is selected from the group consisting of a vial, a bottle, anampule, and a syringe. In some embodiments, the vial is a glass vial ora plastic vial made of polyethylene, polypropylene, polyolefins,polyethylene terephthalate, polyethylene terephthalate G, poly(vinylchloride), and mixtures thereof. In some embodiments, the container hasa volume of 1 mL, 2 mL, 3 mL, 4 mL, or 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or10 mL. In some embodiments, the container is a 3 mL polypropylene vial.

In some embodiments of the process provided herein, the mixing is doneaseptically.

In some embodiments of the process provided herein, the filling is doneaseptically.

In some embodiments, the process further comprises terminallysterilizing the filled container containing the suspension. In someembodiments, the container is terminally sterilized when the suspensioncomprises about 0.05 mg/mL to about 10 mg/mL of the compound of Formula(I) or a salt or amorphous or polymorph form thereof. For example, thesuspension comprises about 0.05 mg/mL to about 5 mg/mL, about 0.05 mg/mLto about 2.5 mg/mL, about 0.05 mg/mL to about 1 mg/mL, about 0.05 mg/mLto about 0.5 mg/mL, about 0.05 mg/mL to about 0.1 mg/mL, about 0.1 mg/mLto about 10 mg/mL, about 0.1 mg/mL to about 5 mg/mL, about 0.1 mg/mL toabout 2.5 mg/mL, about 0.1 mg/mL to about 1 mg/mL, about 0.1 mg/mL toabout 0.5 mg/mL, about 0.1 mg/mL to about 0.25 mg/mL, about 0.25 mg/mLto about 10 mg/mL, about 0.25 mg/mL to about 5 mg/mL, about 0.25 mg/mLto about 2.5 mg/mL, about 0.25 mg/mL to about 1 mg/mL, about 0.25 mg/mLto about 0.5 mg/mL, bout 0.5 mg/mL to about 10 mg/mL, about 0.5 mg/mL toabout 5 mg/mL, about 0.5 mg/mL to about 2.5 mg/mL, about 0.5 mg/mL toabout 1 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 5mg/mL, about 1 mg/mL to about 2.5 mg/mL, about 2.5 mg/mL to about 10mg/mL, about 2.5 mg/mL to about 5 mg/mL, or about 5 mg/mL to about 10mg/mL of the compound of Formula (I) or a salt or amorphous or polymorphform thereof.

Also provided herein is a single-dose, ready-to-use formulationcomprising a compound of Formula (I)

or a pharmaceutically acceptable salt or amorphous or polymorph formthereof, prepared by a process comprising:

(a) providing an aqueous solution comprising water;

(b) providing a slurry comprising a compound of Formula (I), or apharmaceutically acceptable salt or amorphous or polymorph form thereof;

(c) mixing the aqueous solution and the slurry to form a suspension; and

(d) filling a container with the suspension to prepare a single-dose,ready-to-use formulation.

The single-dose, ready-to-use formulation prepared by the processprovided herein comprises providing an aqueous solution comprisingwater. In some embodiments, the aqueous solution comprises a buffer. Insome embodiments, the aqueous buffer is a phosphate buffer. In someembodiments, the phosphate buffer is selected from the group consistingof sodium phosphate dibasic, sodium phosphate monobasic, potassiumphosphate monobasic, potassium phosphate dibasic, and mixtures thereof.In some embodiments, the phosphate buffer is a mixture of sodiumphosphate dibasic heptahydrate and sodium phosphate monobasicmonohydrate. In some embodiments, the buffer is phosphate bufferedsaline.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the aqueous solution comprisesan excipient. In some embodiments, the excipient comprises a surfactant,a viscosity enhancer, or a mixture thereof. In some embodiments, theviscosity enhancer is a cellulose derivative. In some embodiments, thecellulose derivative is a water-soluble cellulose derivative. In someembodiments, the cellulose derivative is sodium carboxymethylcellulose.In some embodiments, the aqueous solution comprises about 0.01 g/kg toabout 50 g/kg; about 0.5 g/kg to about 50 g/kg; about 1.0 g/kg to about50 g/kg; about 1 g/kg to about 25 g/kg; about 1 g/kg to about 10 g/kg;about 1 g/kg to about 7.5 g/kg; about 1 g/kg to about 5.5 g/kg; about 1g/kg to about 2.5 g/kg; about 2.5 g/kg to about 50 g/kg; about 5 g/kg toabout 50 g/kg; about 10 g/kg to about 50 g/kg; about 25 g/kg to about 50g/kg; about 0.1 g/kg to about 5 g/kg; about 2.5 g/kg to about 7.5 g/kg;about 5 g/kg to about 10 g/kg; or about 10 g/kg to about 20 g/kg of aviscosity enhancer. In some embodiments, the aqueous solution comprisesabout 5.5 g/kg of a cellulose derivative.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the surfactant is apolysorbate. In some embodiments, the aqueous solution comprises about0.1 g/kg to about 5 g/kg; 0.1 g/kg to about 2.5 g/kg; about 0.1 g/kg toabout 1 g/kg; about 0.1 g/kg to about 0.75 g/kg; about 0.1 g/kg to about0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg; about 0.25 g/kg to about 5g/kg; about 0.5 g/kg to about 5 g/kg; about 1 g/kg to about 5 g/kg;about 0.1 g/kg to about 5 g/kg; 0.1 g/kg to about 2.5 g/kg; about 0.1g/kg to about 1 g/kg; about 0.1 g/kg to about 0.75 g/kg; about 0.1 g/kgto about 0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg; about 0.25 g/kg toabout 5 g/kg; about 0.25 g/kg to about 2.5 g/kg; about 0.25 g/kg toabout 0.75 g/kg; about 0.5 g/kg to about 2.5 g/kg; about 0.5 g/kg toabout 1 g/kg; or about 1 g/kg to about 2 g/kg of a surfactant. In someembodiments, the aqueous solution comprises about 0.5 g/kg of asurfactant. In some embodiments, the aqueous solution comprises about5.55 g/kg of sodium carboxymethylcellulose and about 0.5 g/kg ofpolysorbate 80.

The single-dose, ready-to-use formulation prepared by the processprovided herein comprises providing a slurry comprising a compound ofFormula (I), or a pharmaceutically acceptable salt or amorphous orpolymorph form thereof. In some embodiments of the process providedherein, the slurry comprises about 0.001 g/kg to about 5 g/kg; about0.001 g/kg to about 2.5 g/kg; about 0.001 g/kg to about 1 g/kg; about0.001 g/kg to about 0.75 g/kg; about 0.001 g/kg to about 0.5 g/kg; about0.001 g/kg to about 0.25 g/kg; about 0.001 g/kg to about 0.01 g/kg;about 0.01 g/kg to about 5 g/kg; about 0.01 g/kg to about 2.5 g/kg;about 0.01 g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75 g/kg;about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25 g/kg;about 0.1 g/kg to about 2.5 g/kg; about 0.1 g/kg to about 1 g/kg; about0.1 g/kg to about 0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg; about 0.1g/kg to about 0.25 g/kg; about 0.25 g/kg to about 5 g/kg; about 0.5 g/kgto about 5 g/kg; about 1 g/kg to about 5 g/kg; about 2.5 g/kg to about 5g/kg; about 0.25 g/kg to about 0.75 g/kg; about 0.5 g/kg to about 1g/kg; or about 1 g/kg to about 2 g/kg of the compound of Formula (I), ora salt or amorphous or polymorph form thereof. In some embodiments, theslurry comprises about 0.15 g/kg, about 0.35 g/kg, or about 1.15 g/kg ofthe compound of Formula (I), or a salt or amorphous or polymorph formthereof. In some embodiments, the compound of Formula (I) comprises apolymorph form. In some embodiments, the polymorph is Form 1 and has anX-ray powder diffraction pattern comprising peaks at ° 2θ values of6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, the compound ofFormula (I) comprises a mixture of a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the compound comprises no more than5% by weight of other Forms. For example, not more than 1% or less than0.1% of another Form, including amorphous.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the slurry comprises anexcipient. In some embodiments, the excipient comprises a surfactant. Insome embodiments, the surfactant is a polysorbate. In some embodiments,the slurry comprises about 0.01 g/kg to about 5 g/kg; 0.01 g/kg to about2.5 g/kg; about 0.01 g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75g/kg; about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25g/kg; about 0.025 g/kg to about 5 g/kg; about 0.05 g/kg to about 5 g/kg;about 1 g/kg to about 5 g/kg; about 0.1 g/kg to about 5 g/kg; 0.1 g/kgto about 2.5 g/kg; about 0.1 g/kg to about 1 g/kg; about 0.1 g/kg toabout 0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg; about 0.1 g/kg toabout 0.25 g/kg; about 0.25 g/kg to about 5 g/kg; about 0.25 g/kg toabout 2.5 g/kg; about 0.25 g/kg to about 0.75 g/kg; about 0.5 g/kg toabout 5 g/kg; about 0.5 g/kg to about 2.5 g/kg; about 0.5 g/kg to about1 g/kg; about 1 g/kg to about 5 g/kg; about 2.5 g/kg to about 5 g/kg; orabout 1 g/kg to about 2 g/kg of a surfactant. In some embodiments, theslurry comprises about 0.5 g/kg of a surfactant.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the slurry comprises about 0.15g/kg of polymorph Form 1 or a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water andabout 0.5 g/kg of polysorbate 80. In some embodiments, the slurrycomprises about 0.35 g/kg of polymorph Form 1 or a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water and about 0.5 g/kg of polysorbate 80. In some embodiments,the slurry comprises about 1.15 g/kg of polymorph Form 1 or anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water and about 0.5 g/kg of polysorbate 80.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the aqueous solution is afiltered mixture. In some embodiments, the filtered mixture compriseswater. In some embodiments, the filtered mixture comprises water and anexcipient. In some embodiments, the excipient comprises a surfactant, aviscosity enhancer, or a mixture thereof.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the aqueous solution comprisesa sterile diluent.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the aqueous solution is asterile-filtered mixture or a first bulk sterilized mixture or both; theslurry is a second bulk sterilized mixture; and the process comprisesmixing the first bulk sterilized mixture and the second bulk sterilizedmixture.

Provided herein is a single-dose, ready-to-use formulation prepared by aprocess comprising mixing the aqueous solution and the slurry to form asuspension. In some embodiments, the aqueous solution and slurry aremixed to form a suspension comprising about 0.005 mg/mL to about 2.5mg/mL, about 0.001 mg/mL to about 2 mg/mL, about 0.01 mg/mL to about 2.0mg/mL, about 0.01 mg/mL to about 1 mg/mL, about 0.01 mg/mL to about 0.5mg/mL, about 0.01 mg/mL to about 0.2 mg/mL, or about 0.015 mg/mL toabout 0.115 mg/mL of the compound of Formula (I) or a salt or amorphousor polymorph form thereof.

Provided herein is a single-dose, ready-to-use formulation prepared by aprocess comprising filling a container with the suspension to prepare asingle-dose, ready-to-use formulation. In some embodiments, thecontainer comprises a suspension comprising about 0.005 mg/mL to about2.5 mg/mL, about 0.005 mg/mL to about 2 mg/mL, about 0.01 mg/mL to about1.8 mg/mL, about 0.015 mg/mL to about 0.115, about 0.025 mg/mL to about1.6 mg/mL, about 0.05 mg/mL to about 1.5 mg/mL, about 0.075 mg/mL toabout 1.25 mg/mL, about 0.1 mg/mL to about 1 mg/mL, or about 0.25 mg/mLto about 0.75 mg/mL of the compound of Formula (I) or a salt oramorphous or polymorph form thereof. In some embodiments, the containeris selected from the group consisting of a vial, a bottle, an ampule,and a syringe. In some embodiments, the vial is a glass vial or aplastic vial made of polyethylene, polypropylene, polyolefins,polyethylene terephthalate, polyethylene terephthalate G, poly(vinylchloride), and mixtures thereof. In some embodiments, the container hasa volume of 1 mL, 2 mL, 3 mL, 4 mL, or 5 mL. In some embodiments, thecontainer is a 3 mL polypropylene vial.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the mixing is done aseptically.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the filling is doneaseptically.

In some embodiments of the single-dose, ready-to-use formulationprepared by the process provided herein, the container containing thesuspension is terminally sterilized. In some embodiments, the containeris terminally sterilized when the suspension comprises about 0.05 mg/mLto about 10 mg/mL of the compound of Formula (I) or a salt or amorphousor polymorph form thereof. For example, the suspension comprises about0.05 mg/mL to about 5 mg/mL, about 0.05 mg/mL to about 2.5 mg/mL, about0.05 mg/mL to about 1 mg/mL, about 0.05 mg/mL to about 0.5 mg/mL, about0.05 mg/mL to about 0.1 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about0.1 mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about0.1 mg/mL to about 1 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about0.1 mg/mL to about 0.25 mg/mL, about 0.25 mg/mL to about 10 mg/mL, about0.25 mg/mL to about 5 mg/mL, about 0.25 mg/mL to about 2.5 mg/mL, about0.25 mg/mL to about 1 mg/mL, about 0.25 mg/mL to about 0.5 mg/mL, bout0.5 mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5mg/mL to about 2.5 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 1mg/mL to about 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mLto about 2.5 mg/mL, about 2.5 mg/mL to about 10 mg/mL, about 2.5 mg/mLto about 5 mg/mL, or about 5 mg/mL to about 10 mg/mL of the compound ofFormula (I) or a salt or amorphous or polymorph form thereof.

Also provided herein is a method for treating osteoarthritis in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the single-dose, ready-to-useformulation prepared by the process provided herein that comprises atherapeutically effective amount of a compound of Formula (I), includingsalt and amorphous and polymorph forms thereof. In some embodiments,administration of the formulation is intra-articular. In someembodiments, the formulation is administered to the subject once. Insome embodiments, the formulation is administered more than once witheach injection separated by about 3 months to about 60 months. In someembodiments, the formulation is administered once every 2 weeks, every 3weeks, every 4 weeks, every 6 weeks, every 8 weeks, or every 3 months, 6months, 9 months, 12 months, 18 months, 24 months, 30 months, or 60months.

Other features and advantages of the processes, formulations, and usesprovided herein will be apparent from the following detailed descriptionand figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1D are scans of polymorph Form 1 of the compound of Formula(I). FIG. 1A is an x-ray powder diffraction scan of fully dried Form 1.FIG. 1B is a differential scanning calorimetry scan of Form 1. FIG. 1Cis a thermal gravimetric analysis scan of Form 1. FIG. 1D is a dynamicvapor sorption scan of Form 1.

FIGS. 2A-2H are scans of polymorph Forms 2, 2*, and 2** of the compoundof Formula (I). FIG. 2A is an x-ray powder diffraction scan of fullydried Form 2. FIG. 2B is a differential scanning calorimetry scan ofForm 2. FIG. 2C is a thermal gravimetric analysis scan of Form 2. FIG.2D is an x-ray powder diffraction scan of fully dried Form 2*. FIG. 2Eis a differential scanning calorimetry scan of Form 2*. FIG. 2F is athermal gravimetric analysis scan of Form 2*. FIG. 2G is an x-ray powderdiffraction scan of Form 2**. FIG. 2H is a differential scanningcalorimetry scan of Form 2**.

FIGS. 3A-3C are scans of polymorph Form 3 of the compound of Formula(I). FIG. 3A is an x-ray powder diffraction scan of fully dried Form 3.FIG. 3B is a differential scanning calorimetry scan of Form 3. FIG. 3Cis a thermal gravimetric analysis scan of Form 3.

FIGS. 4A-4I are scans of polymorph Forms 4, 4*, and 4** of the compoundof Formula (I). FIG. 4A is an x-ray powder diffraction scan of fullydried Form 4. FIG. 4B is a differential scanning calorimetry scan ofForm 4. FIG. 4C is a thermal gravimetric analysis scan of Form 4. FIG.4D is an x-ray powder diffraction scan of fully dried Form 4*. FIG. 4Eis a differential scanning calorimetry scan of Form 4*. FIG. 4F is athermal gravimetric analysis scan of Form 4*. FIG. 4G is an x-ray powderdiffraction scan of Form 4**. FIG. 4H is a differential scanningcalorimetry scan of Form 4**. FIG. 4I is a thermal gravimetric analysisscan of Form 4**.

FIGS. 5A-5D are scans of polymorph Forms 5 and 5* of the compound ofFormula (I). FIG. 5A is an x-ray powder diffraction scan of fully driedForm 5. FIG. 5B is a differential scanning calorimetry scan of Form 5.FIG. 5C is a thermal gravimetric analysis scan of Form 5. FIG. 5D is anx-ray powder diffraction scan of Form 5*.

FIGS. 6A and 6B are scans of polymorph Form 6 of the compound of Formula(I). FIG. 6A is an x-ray powder diffraction scan of Form 6. FIG. 6B is adifferential scanning calorimetry scan of Form 6.

FIGS. 7A-7C are scans of polymorph Form 7 of the compound of Formula(I). FIG. 7A is an x-ray powder diffraction scan of fully dried Form 7.FIG. 7B is a differential scanning calorimetry scan of Form 7. FIG. 7Cis a thermal gravimetric analysis scan of Form 7.

FIGS. 8A-8C are scans of polymorph Form 8 of the compound of Formula(I). FIG. 8A is an x-ray powder diffraction scan of fully dried Form 8.FIG. 8B is a differential scanning calorimetry scan of Form 8. FIG. 8Cis a thermal gravimetric analysis scan of Form 8.

FIGS. 9A-9D are scans of polymorph Form 9 of the compound of Formula(I). FIG. 9A is an x-ray powder diffraction scan of fully dried Form 9.FIG. 9B is a differential scanning calorimetry scan of Form 9. FIG. 9Cis a thermal gravimetric analysis scan of Form 9. FIG. 9D is a dynamicvapor sorption scan of Form 9.

FIGS. 10A-10E are scans of polymorph Forms 10 and 10* of the compound ofFormula (I). FIG. 10A is an x-ray powder diffraction scan of fully driedForm 10. FIG. 10B is a differential scanning calorimetry scan of Form10. FIG. 10C is a thermal gravimetric analysis scan of Form 10. FIG. 10Dis an x-ray powder diffraction scan of Form 10*. FIG. 10E is adifferential scanning calorimetry scan of Form 10*.

FIGS. 11A-11F are scans of polymorph Forms 11 and 11* of the compound ofFormula (I). FIG. 11A is an x-ray powder diffraction scan of fully driedForm 11. FIG. 11B is a differential scanning calorimetry scan of Form11. FIG. 11C is a thermal gravimetric analysis scan of Form 11. FIG. 11Dis an x-ray powder diffraction scan of fully dried Form 11*. FIG. 11E isa differential scanning calorimetry scan of Form 11*. FIG. 11F is athermal gravimetric analysis scan of Form 11*.

FIGS. 12A-12C are scans of Form 12, an example of a non-stoichiometrichydrate of polymorph Form 1 of the compound of Formula (I). FIG. 12A isan x-ray powder diffraction scan of Form 12. FIG. 12B is a differentialscanning calorimetry scan of Form 12. FIG. 12C is a thermal gravimetricanalysis scan of Form 12.

FIGS. 13A-13D are scans of Form 13, an example of a non-stoichiometrichydrate of polymorph Form 1 of the compound of Formula (I). FIG. 13A isan x-ray powder diffraction scan of Form 13. FIG. 13B is a differentialscanning calorimetry scan of Form 13. FIG. 13C is a thermal gravimetricanalysis scan of Form 13. FIG. 13D is a dynamic vapor sorption scan ofForm 13.

FIG. 14 is a flow chart showing an exemplary process described herein.

FIGS. 15A-15D are scans of Form 1 in the presence of increasing relativehumidity (RH), an example of a non-stoichiometric or stoichiometrichydrate of polymorph Form 1 of the compound of Formula (I). FIG. 15A isan x-ray powder diffraction scan of Form 1 exposed to 10% RH as theanhydrous Form 1. FIG. 15B is an x-ray powder diffraction scan of Form 1exposed to 20% RH as a partial hydrate of Form 1. FIG. 15C is an x-raypowder diffraction scan of Form 1 exposed to 30% RH as a hydrate of Form1 (≈10-12% water uptake). FIG. 15D is an x-ray powder diffraction scanof Form 1 exposed to 90% RH as a full hydrate of Form 1 (≈17-20% wateruptake).

DETAILED DESCRIPTION 1. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Methods and materials aredescribed herein for use in the present disclosure; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, co-solvents,complexing agents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike, which are not biologically or otherwise undesirable. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticformulations is contemplated. Supplementary active ingredients can alsobe incorporated into the formulations. In addition, various excipients,such as are commonly used in the art, can be included. These and othersuch compounds are described in the literature, e.g., in the MerckIndex, Merck & Company, Rahway, NJ Considerations for the inclusion ofvarious components in pharmaceutical compositions are described, e.g.,in Gilman et al. (Eds.) (2010); Goodman and Gilman's: ThePharmacological Basis of Therapeutics, 12th Ed., The McGraw-HillCompanies.

As used herein, a “single-dose” refers to a sterile formulation that ispackaged in a container for parenteral administration (injection orinfusion). A single-dose formulation is designed for use with a singlepatient as a single injection/infusion. Examples of containers for usewith single-dose formulations include vials, ampules, bottles, andsyringes.

“Ready-to-use,” as used herein, refers to a formulation that does notrequire constitution or dilution with a prescribed amount of diluent,e.g., water for injection or other suitable diluent, before use by thedesignated route. For example, a formulation in a vial, of the desiredconcentration, that only needs to be drawn up into a syringe.

The term “polymorph,” as used herein, refers to crystals of the samemolecule having different physical properties as a result of the orderof the molecules in the crystal lattice. Polymorphs of a single compoundhave one or more different chemical, physical, mechanical, electrical,thermodynamic, and/or biological properties from each other. Differencesin physical properties exhibited by polymorphs can affect pharmaceuticalparameters such as storage stability, compressibility, density(important in composition and product manufacturing), dissolution rates(an important factor in determining bio-availability), solubility,melting point, chemical stability, physical stability, powderflowability, water sorption, compaction, and particle morphology.Differences in stability can result from changes in chemical reactivity(e.g. differential oxidation, such that a dosage form discolors morerapidly when comprised of one polymorph than when comprised of anotherpolymorph) or mechanical changes (e.g., crystal changes on storage as akinetically favored polymorph converts to a thermodynamically morestable polymorph) or both (e.g., one polymorph is more hygroscopic thanthe other). As a result of solubility/dissolution differences, sometransitions affect potency and/or toxicity. In addition, the physicalproperties of the crystal may be important in processing; for example,one polymorph might be more likely to form solvates or might bedifficult to filter and wash free of impurities (i.e., particle shapeand size distribution might be different between one polymorph relativeto the other). “Polymorph” does not include amorphous forms of thecompound. As used herein, “amorphous” refers to a non-crystalline formof a compound which may be a solid state form of the compound or asolubilized form of the compound. For example, “amorphous” refers to acompound without a regularly repeating arrangement of molecules orexternal face planes.

The term “anhydrous,” as used herein, refers to a crystal form of thecompound of Formula (I) that has 1% or less by weight water. Forexample, 0.5% or less, 0.25% or less, or 0.1% or less by weight water.

The term “solvate” as used herein refers to a crystalline form of acompound of Formula (I), such as a polymorph form of the compound, wherethe crystal lattice comprises one or more solvents of crystallization.

The term “non-stoichiometric hydrate” refers to a crystalline form of acompound of Formula I that comprises water, but wherein variations inthe water content do not cause significant changes to the crystalstructure. In some embodiments, a non-stoichiometric hydrate can referto a crystalline form of a compound of Formula I that has channels ornetworks throughout the crystal structure into which water molecules candiffuse. During drying of non-stoichiometric hydrates, a considerableproportion of water can be removed without significantly disturbing thecrystal network, and the crystals can subsequently rehydrate to give theinitial non-stoichiometric hydrated crystalline form. Unlikestoichiometric hydrates, the dehydration and rehydration ofnon-stoichiometric hydrates is not accompanied by a phase transition,and thus all hydration states of a non-stoichiometric hydrate representthe same crystal form. In some embodiments, a non-stoichiometric hydratecan have up to about 20% by weight water, such as, about 20%, about 19%,about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about5%, about 4%, about 3%, about 2%, or greater than 1% water by weight. Insome embodiments, a non-stoichiometric hydrate can have between 1% andabout 20% by weight water, such as between 1% and about 5%, 1% and about10%, 1% and about 15%, about 2% and about 5%, about 2% and about 10%,about 2% and about 15%, about 2% and about 20%, about 5% and about 10%,about 5% and about 15%, about 5% and about 20%, about 10% and about 15%,about 10% and about 20%, or about 15% and about 20% by weight water.

In some embodiments the % water by weight in a crystal form, such as anon-stoichiometric or stoichiometric hydrate, is determined by the KarlFischer titration method. In some embodiments, the crystal form is driedprior to Karl Fischer titration.

“Purity,” when used in reference to a composition including a polymorphof a compound of Formula (I), refers to the percentage of one specificpolymorph form relative to another polymorph form or an amorphous formof a compound of Formula (I) in the referenced composition. For example,a composition comprising polymorph Form 1 having a purity of 90% wouldcomprise 90 weight parts Form 1 and 10 weight parts of other polymorphand/or amorphous forms of the compound of Formula (I).

As used herein, a compound or composition is “substantially free of” oneor more other components if the compound or composition contains nosignificant amount of such other components. Such components can includestarting materials, residual solvents, or any other impurities that canresult from the preparation of and/or isolation of the compounds andcompositions provided herein. In some embodiments, a polymorph formprovided herein is substantially free of other polymorph forms. In someembodiments, a particular polymorph of the compound of Formula (I) is“substantially free” of other polymorphs if the particular polymorphconstitutes at least about 95% by weight of the compound of Formula (I)present. In some embodiments, a particular polymorph of the compound ofFormula (I) is “substantially free” of other polymorphs if theparticular polymorph constitutes at least about 97%, about 98%, about99%, or about 99.5% by weight of the compound of Formula (I) present. Incertain embodiments, a particular polymorph of the compound of Formula(I) is “substantially free” of water if the amount of water constitutesno more than about 2%, about 1%, or about 0.5% by weight of thepolymorph.

As used herein, a compound is “substantially present” as a givenpolymorph if at least about 50% by weight of the compound is in the formof that polymorph. In some embodiments, at least about 60% by weight ofthe compound is in the form of that polymorph. In some embodiments, atleast about 70% by weight of the compound is in the form of thatpolymorph. In some embodiments, at least about 80% by weight of thecompound is in the form of that polymorph. In some embodiments, at leastabout 90% by weight of the compound is in the form of that polymorph. Insome embodiments, at least about 95% by weight of the compound is in theform of that polymorph. In some embodiments, at least about 96% byweight of the compound is in the form of that polymorph. In someembodiments, at least about 97% by weight of the compound is in the formof that polymorph. In some embodiments, at least about 98% by weight ofthe compound is in the form of that polymorph. In some embodiments, atleast about 99% by weight of the compound is in the form of thatpolymorph. In some embodiments, at least about 99.5% by weight of thecompound is in the form of that polymorph.

“Room temperature” or “RT” refers to the ambient temperature of atypical laboratory, which is typically around 25° C.

The term “administration” or “administering” refers to a method ofgiving a dosage of a compound or pharmaceutical formulation to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian. The preferred method of administration can vary depending onvarious factors, e.g., the components of the pharmaceutical formulation,the site of the disease, and the severity of the disease.

“Subject,” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate. In some embodiments, the subject is a human.

As used herein, “therapeutically effective amount” is an amount of theformulation provided herein comprising a compound of Formula (I), orsalt or amorphous or polymorph form thereof, which is sufficient toachieve the desired effect and can vary according to the nature andseverity of the disease condition, and the potency of the compound. Atherapeutic effect is the relief, to some extent, of one or more of thesymptoms of the disease, and can include curing a disease. “Curing”means that the symptoms of active disease are eliminated. However,certain long-term or permanent effects of the disease can exist evenafter a cure is obtained (such as, e.g., extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein, refers toadministering a compound or pharmaceutical formulation as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from adisease, thus causing a therapeutically beneficial effect, such asameliorating existing symptoms, preventing additional symptoms,ameliorating the underlying metabolic causes of symptoms, postponing orpreventing the further development of a disorder and/or reducing theseverity of symptoms that will or are expected to develop.

2. Process for Preparing Single-Dose, Ready-to-Use Formulations

Provided herein is a process for preparing a single-dose, ready-to-useformulation comprising a compound of Formula (I)

including salts and amorphous and polymorph forms thereof. The processincludes:

(a) providing an aqueous solution comprising water;

(b) providing a slurry comprising a compound of Formula (I), includingsalts and amorphous and polymorph forms thereof;

(c) mixing the aqueous solution and slurry to form a suspension; and

(d) aseptically filling a container with the suspension to prepare asingle-dose formulation.

In the process provided herein, the process comprises providing anaqueous solution comprising water. Suitable types of water include, butare not limited to, deionized water, distilled water, reverse osmosisfiltered water, reagent grade water, water for injection (WFI), USP/EPgrade water suitable for use in pharmaceuticals, and aqueous buffersolutions. The water is substantially free of contaminants, such asparasites, pathogens, chemical contaminants, and particulatecontamination. In some embodiments, the aqueous solution comprises abuffer. In some embodiments, the aqueous solution comprises anexcipient. In some embodiments, the aqueous solution comprises a bufferand an excipient. In some embodiments, the excipient comprises asurfactant. In some embodiments, the excipient comprises a viscosityenhancer. In some embodiments, the excipient comprises a surfactant, aviscosity enhancer, or a mixture thereof. For example, the aqueoussolution can include a surfactant and a viscosity enhancer in an aqueousbuffer. In some embodiments, the viscosity enhancer is a cellulosederivative. In some embodiments, the aqueous solution comprises about5.55 g/kg of sodium carboxymethylcellulose and about 0.5 g/kg ofpolysorbate 80 in phosphate buffered saline.

In some embodiments of the process provided herein, the aqueous solutionincludes a viscosity enhancer. The viscosity enhancer can be, forexample, a cellulose or cellulose derivative or a synthetic polymer.Examples of viscosity enhancers include, but are not limited to,microcrystalline cellulose (Avicel: Asahi Kasei Corp., etc.),microcrystalline cellulose carmellose sodium (Avicel RC: Asahi KaseiCorp., etc.), methyl cellulose (Metolose SM: Shin-Etsu Chemical Co.,Ltd., etc.), ethyl cellulose (Ethocel: Dow Chemical Co., etc.),hydroxypropyl cellulose (Nisso HPC: Nippon Soda Co., Ltd., etc.),low-substituted hydroxypropyl cellulose (L-HPC: Shin-Etsu Chemical Co.,Ltd., etc.), hydroxypropyl methyl cellulose 2208 (Metolose 90SH:Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methyl cellulose 2906(Metolose 65SH: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropylmethyl cellulose 2910 (Metolose 60SH: Shin-Etsu Chemical Co., Ltd.,etc.), hydroxypropyl cellulose phthalate 200731 (HPMCP: Shin-EtsuChemical Co., Ltd., etc.), hydroxypropyl cellulose phthalate 220824(HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQOAT: Shin-Etsu Chemical Co.,Ltd., etc.), carmellose (NS-300: Gotoku Chemical Co., Ltd., etc.),carmellose calcium (ECG-505: Gotoku Chemical Co., Ltd., etc.),carmellose sodium (Cellogen: Daiichi Kogyo Seiyaku Co., Ltd., etc.),croscarmellose sodium (Ac-Di-Sol: Asahi Kasei Corp., etc.),carboxymethyl ethyl cellulose (CMEC: Freund Corp., etc.), celluloseacetate phthalate (CAP: Wako Pure Chemical Industries, Ltd., etc.),hydroxyethyl cellulose (NATROSOL: Aqualon Corp., etc.), polyvinylalcohol, polyvinylpyrrolidone, or mixtures thereof. In some embodiments,the viscosity enhancer is a cellulose derivative. In some embodiments,the cellulose derivative is a water-soluble cellulose or water-solublecellulose derivative. In some embodiments, the cellulose derivative is acarboxymethylcellulose, or a pharmaceutically acceptable salt thereof.For example, the aqueous solution comprises sodiumcarboxymethylcellulose.

A viscosity enhancer can be present in the aqueous solution in an amountof about 0.01 g/kg to about 50 g/kg of the aqueous solution. Forexample, about 0.01 g/kg to about 25 g/kg; about 0.01 g/kg to about 5g/kg; about 0.1 g/kg to about 50 g/kg; about 0.1 g/kg to about 25 g/kg;about 0.1 g/kg to about 5 g/kg; about 0.5 g/kg to about 50 g/kg; about0.5 g/kg to about 0.25 g/kg; about 0.5 g/kg to about 10 g/kg; about 0.5g/kg to about 7.5 g/kg; about 0.5 g/kg to about 5.5 g/kg; about 0.5 g/kgto about 2.5 g/kg; about 1 g/kg to about 50 g/kg; about 1 g/kg to about25 g/kg; about 1 g/kg to about 10 g/kg; about 1 g/kg to about 7.5 g/kg;about 1 g/kg to about 5.5 g/kg; about 1 g/kg to about 2.5 g/kg; about2.5 g/kg to about 50 g/kg; about 5 g/kg to about 50 g/kg; about 10 g/kgto about 50 g/kg; about 25 g/kg to about 50 g/kg; about 0.1 g/kg toabout 5 g/kg; about 2.5 g/kg to about 7.5 g/kg; about 5 g/kg to about 10g/kg; and about 10 g/kg to about 20 g/kg of the aqueous solution. Insome embodiments, the viscosity enhancer can be present in the aqueoussolution at about 5 g/kg of the aqueous solution. In some embodiments,the viscosity enhancer can be present in the aqueous solution at about5.55 g/kg of the aqueous solution. For example, the aqueous solutioncomprises about 5.55 g/kg sodium carboxymethylcellulose. In someembodiments, a cellulose derivative is present in the aqueous solutionin an amount of about 0.05% to about 5% by weight of the aqueoussolution. For example, about 0.05% to about 2.5%; about 0.05% to about1%; about 0.05% to about 0.75%; about 0.05% to about 0.55%; about 0.05%to about 0.25%; about 0.1% to about 5%; about 0.1% to about 2.5%; about0.1% to about 1%; about 0.1% to about 0.75%; about 0.1% to about 0.55%;about 0.1% to about 0.25%; about 0.25% to about 5%; about 0.5% to about5%; about 1% to about 5%; about 2.5% to about 5%; about 0.25% to about0.75%; about 0.5% to about 1%; and about 1% to about 2% by weight of theaqueous solution. In some embodiments, the viscosity enhancer can bepresent in the aqueous solution at about 0.55% by weight of the aqueoussolution. For example, the aqueous solution comprises about 0.55% sodiumcarboxymethylcellulose by weight.

In some embodiments of the process provided herein, the aqueous solutionincludes a surfactant. Examples of surfactants include, but are notlimited to, polysorbates such as polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylenehydrogenated castor oils such as polyoxyethylene hydrogenated castor oil60 and polyoxyl 35 castor oil; sorbitan fatty acid esters; sucrose fattyacid esters; polyoxyethylene polyoxypropylene glycols; polyoxyethylenefatty acid ethers; polyoxyl stearates; phosphatidylcholines;phosphatidylglycerols, including, but not limited tophosphatidylglycerols containing fatty acids, fatty alcohols, or acombination thereof, and carbon chain lengths between 4 and 20 carbons;and other surfactants, including, but not limited to,1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)),1,2-dioleoyl-sn-glycero-3-phosphocholine,1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)),1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)),1,2-distearoyl-sn-glycero-3-phosphocholine, deoxycholic acid,dipalmitoylphosphatidylglycerol (dl), distearoylphosphatidylcholine(dl), docusate sodium, egg phospholipids, glyceryl palmitostearate,glyceryl trioleate, hydrogenated soybean lecithin, hydrolyzed soyprotein (enzymatic; 2000 mw), hydroxyethylpiperazine ethane sulfonicacid, lecithin, miripirium chloride, n-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, oleic acid, palmiticacid, peg vegetable oil, peg-20 sorbitan isostearate, peg-40 castor oil,phospholipid, poloxamer 188, polyethylene glycol 200, polyethyleneglycol 300, polyethylene glycol 3350, polyethylene glycol 400,polyethylene glycol 4000, polyethylene glycol 600, polyoxyethylene fattyacid esters, sodium cholesteryl sulfate, sodium deoxycholate, sodiumn-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glyc,sodium oleate, sorbitan monolaurate, sorbitan monopalmitate, stearicacid, tricaprylin, or mixtures thereof. In some embodiments, thesurfactant is a polysorbate. For example, the aqueous solution comprisespolysorbate 80.

A surfactant can be present in the aqueous solution in an amount ofabout 0.01 g/kg to about 5 g/kg of the aqueous solution. In someembodiments, the concentration of surfactant depends on the criticalmicelle concentration of the individual surfactant. In some embodiments,the amount of surfactant is enough to be above the critical micelleconcentration of the surfactant, enough to coat the surface area of theparticles, or both. For example, about 0.01 g/kg to about 2.5 g/kg;about 0.01 g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75 g/kg;about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25 g/kg;about 0.025 g/kg to about 5 g/kg; about 0.05 g/kg to about 5 g/kg; about1 g/kg to about 5 g/kg; about 0.1 g/kg to about 5 g/kg; about 0.1 g/kgto about 2.5 g/kg; about 0.1 g/kg to about 1 g/kg; about 0.1 g/kg toabout 0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg; about 0.1 g/kg toabout 0.25 g/kg; about 0.25 g/kg to about 5 g/kg; about 0.5 g/kg toabout 5 g/kg; about 1 g/kg to about 5 g/kg; about 0.25 g/kg to about 5g/kg; about 0.25 g/kg to about 2.5 g/kg; about 0.25 g/kg to about 0.75g/kg; about 0.5 g/kg to about 2.5 g/kg; about 0.5 g/kg to about 1 g/kg;and about 1 g/kg to about 2 g/kg of the aqueous solution. In someembodiments, the surfactant can be present in the aqueous solution atabout 0.5 g/kg of the aqueous solution. For example, the aqueoussolution comprises about 0.5 g/kg polysorbate 80. In some embodiments, asurfactant can be present in the aqueous solution in an amount of about0.001% to about 0.5% by weight of the aqueous solution. For example,about 0.001% to about 0.25%; about 0.001% to about 0.1%; about 0.001% toabout 0.075%; about 0.001% to about 0.05%; about 0.001% to about 0.025%;about 0.0025% to about 0.5%; about 0.005% to about 0.5%; about 0.1% toabout 0.5%; about 0.01% to about 0.5%; about 0.01% to about 0.25%; about0.01% to about 0.1%; about 0.01% to about 0.075%; about 0.01% to about0.05%; about 0.01% to about 0.025%; about 0.025% to about 0.5%; about0.05% to about 0.5%; about 0.1% to about 0.5%; about 0.025% to about0.5%; about 0.025% to about 2.5%; about 0.025% to about 0.075%; about0.05% to about 2.5%; about 0.05% to about 0.1%; and about 0.1% to about0.2% by weight of the aqueous solution. In some embodiments, thesurfactant can be present in the aqueous solution at about 0.05% byweight of the aqueous solution. For example, the aqueous solutioncomprises about 0.05% polysorbate 80 by weight.

In the process provided herein, the process comprises providing a slurrycomprising a compound of Formula (I), including salts and amorphous andpolymorph forms thereof. In some embodiments, the compound of Formula(I) is polymorph Form 1. In some embodiments, the compound of Formula(I) is a non-stoichiometric or stoichiometric hydrate of Form 1 havingbetween 1% and about 20% by weight water. In some embodiments, theslurry comprises a surfactant. In some embodiments, the slurry compriseswater. For example, the slurry can include a compound of Formula (I),including salts and amorphous and polymorph forms thereof and asurfactant in water.

The compound of Formula (I), including salts and amorphous and polymorphforms thereof can be present in the slurry in an amount of about 0.001g/kg to about 5 g/kg of the slurry. For example, about 0.001 g/kg toabout 5 g/kg; about 0.001 g/kg to about 2.5 g/kg; about 0.001 g/kg toabout 1 g/kg; about 0.001 g/kg to about 0.75 g/kg; about 0.001 g/kg toabout 0.5 g/kg; about 0.001 g/kg to about 0.25 g/kg; about 0.001 g/kg toabout 0.01 g/kg; about 0.01 g/kg to about 2.5 g/kg; about 0.01 g/kg toabout 1 g/kg; about 0.01 g/kg to about 0.75 g/kg; about 0.01 g/kg toabout 0.5 g/kg; about 0.01 g/kg to about 0.25 g/kg; about 0.1 g/kg toabout 2.5 g/kg; about 0.1 g/kg to about 1 g/kg; about 0.1 g/kg to about0.75 g/kg; about 0.1 g/kg to about 0.5 g/kg; about 0.1 g/kg to about0.25 g/kg; about 0.25 g/kg to about 5 g/kg; about 0.5 g/kg to about 5g/kg; about 1 g/kg to about 5 g/kg; about 2.5 g/kg to about 5 g/kg;about 0.25 g/kg to about 0.75 g/kg; about 0.5 g/kg to about 1 g/kg; andabout 1 g/kg to about 2 g/kg of the slurry. In some embodiments, thecompound of Formula (I), including salts and amorphous and polymorphforms thereof, can be present in the slurry at about 0.15 g/kg of theslurry. In some embodiments, the compound of Formula (I), includingsalts and amorphous and polymorph forms thereof, can be present in theslurry at about 0.35 g/kg of the slurry. In some embodiments, thecompound of Formula (I), including salts and amorphous and polymorphforms thereof, can be present in the slurry at about 1.15 g/kg of theslurry. In some embodiments, the slurry comprises about 0.15 g/kgpolymorph Form 1 or a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water. In someembodiments, the slurry comprises about 0.35 g/kg polymorph Form 1 or anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the slurry comprisesabout 1.15 g/kg polymorph Form 1 or a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water.

In some embodiments, the compound of Formula (I), including salts andamorphous and polymorph forms thereof, can be present in the slurry inan amount of about 0.0001% to about 0.5% by weight of the slurry. Forexample, about 0.0001% to about 0.5%; about 0.0001% to about 0.25%;about 0.0001% to about 0.1%; about 0.0001% to about 0.075%; about0.0001% to about 0.05%; about 0.0001% to about 0.025%; about 0.0001% toabout 0.001%; about 0.001% to about 0.5%; about 0.001% to about 0.25%;about 0.001% to about 0.1%; about 0.001% to about 0.075%; about 0.001%to about 0.05%; about 0.001% to about 0.025%; about 0.01% to about0.25%; about 0.01% to about 0.1%; about 0.01% to about 0.075%; about0.01% to about 0.05%; about 0.01% to about 0.025%; about 0.025% to about0.5%; about 0.05% to about 0.5%; about 0.1% to about 0.5%; about 0.25%to about 0.5%; about 0.025% to about 0.075%; about 0.05% to about 0.1%;and about 0.1% to about 0.2% by weight of the slurry. In someembodiments, the compound of Formula (I), including salts and amorphousand polymorph forms thereof, can be present in the slurry at about0.015% by weight of the slurry. For example, the slurry comprises about0.015% by weight of polymorph Form 1 or a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the compound of Formula (I),including salts and amorphous and polymorph forms thereof, can bepresent in the slurry at about 0.035% by weight of the slurry. Forexample, the slurry comprises about 0.035% by weight of polymorph Form 1or a non-stoichiometric or stoichiometric hydrate of Form 1 havingbetween 1% and about 20% by weight water. In some embodiments, thecompound of Formula (I), including salts and amorphous and polymorphforms thereof, can be present in the slurry at about 0.115% by weight ofthe slurry. For example, the slurry comprises about 0.115% by weight ofpolymorph Form 1 or a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water.

In some embodiments, the slurry comprises about 0.15 g/kg of a compoundof Formula (I), e.g., Form 1 or a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water andabout 0.5 g/kg of polysorbate 80 in water. In some embodiments, thecompounds has no more than 5% by weight of other Forms. For example, notmore than 1% or less than 0.1% of any additional Form, includingamorphous. In some embodiments, the slurry comprises about 0.35 g/kg ofa compound of Formula (I), e.g., Form 1 or a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water, and about 0.5 g/kg of polysorbate 80 in water. In someembodiments, the slurry comprises about 1.15 g/kg of a compound ofFormula (I), e.g., Form 1 or a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water, andabout 0.5 g/kg of polysorbate 80 in water.

In some embodiments, the slurry comprises water. Suitable types of waterinclude, but are not limited to, deionized water, distilled water,reverse osmosis filtered water, reagent grade water, water for injection(WFI), USP grade water suitable for use in pharmaceuticals, and aqueousbuffer solutions. The water is substantially free of contaminants, suchas parasites, pathogens, chemical contaminants, and particulatecontamination. In some embodiments, the slurry comprises water forinjection.

In the process provided herein, the process comprises mixing the aqueoussolution and slurry to form a suspension. In some embodiments, theaqueous solution is added to the slurry. In some embodiments, the slurryis added to the aqueous solution. In some embodiments, the aqueoussolution and the slurry are added to a container substantially at thesame time.

In some embodiments, the aqueous solution is a filtered mixture. In someembodiments, the filtered mixture comprises water. In some embodiments,the filtered mixture comprises water and an excipient. In someembodiments, the excipient comprises a surfactant, a viscosity enhancer,or a mixture thereof. In some embodiments, the filtered mixture isprepared by filtering the aqueous solution through a 0.2 μm filter. Insome embodiments, the filter comprises a membrane comprising celluloseacetate, cellulose nitrate, nylon, a polymer, such as polyethersulfoneor polytetrafluorethylene, regenerated cellulose, or glass. In someembodiments, the filter membrane is a polymeric membrane. In someembodiments, the filter membrane is a polyethersulfone (PES) membrane.In some embodiments, a sterile diluent is mixed with the filteredmixture.

In some embodiments, the aqueous solution, the slurry, or both, aresterilized. In some embodiments, sterilization is by heat. In someembodiments, sterilization is by bulk steam sterilization. In someembodiments, sterilization is by dry heat sterilization. In someembodiments, sterilization is by irradiation. In some embodiments,sterilization is by filtration. In some embodiments, sterilization is bybulk steam sterilization, dry heat sterilization, irradiation, orcombinations thereof. In some embodiments, the aqueous solution issterilized by filtration or by heat or by a combination of filtrationand heat. In some embodiments, the aqueous solution is sterilized toform a first sterilized mixture prior to mixing with the slurry. In someembodiments, the filtered mixture is sterilized prior to mixing with theslurry. In some embodiments, the filtered mixture is aseptically mixedwith sterile diluent and sterilized prior to mixing with the slurry. Insome embodiments, the slurry is sterilized to form a second sterilizedmixture prior to mixing with the aqueous solution. In some embodiments,the slurry is sterilized by heat. In some embodiments, the aqueoussolution is sterilized to form a first sterilized mixture and the slurryis sterilized to form a second sterilized mixture prior to mixing.

In some embodiments, the aqueous solution and the slurry are mixedaseptically to form a suspension. The mixing can be done with anysterile diluent or solution for injection. For example, any commerciallyavailable sterile diluent or solution for injection can be used. In someembodiments, the sterile solution for injection includes, but is notlimited to, saline, with or without potassium chloride, e.g., a 0.9%saline solution, dextrose, e.g., a 5% dextrose solution, phosphatebuffer, Lactated Ringer's solution, and combinations thereof. In someembodiments, the sterile solution for injection is a commerciallyavailable solution containing hyaluronic acid or hyaluronic acidderivatives. In some embodiments, the sterile diluent is asepticallyadded in an amount sufficient to result in a suspension comprising 0.015mg/mL of the compound of Formula (I) including salts and amorphous andpolymorph forms thereof. In some embodiments, the sterile diluent isaseptically added in an amount sufficient to result in a suspensioncomprising 0.035 mg/mL of the compound of Formula (I) including saltsand amorphous and polymorph forms thereof. In some embodiments, thesterile diluent is aseptically added in an amount sufficient to resultin a suspension comprising 0.115 mg/mL of the compound of Formula (I)including salts and amorphous and polymorph forms thereof.

In the process provided herein, the aqueous solution and slurry aremixed to form a suspension. For example, in some embodiments, thecompound of Formula (I), including salts and amorphous and polymorphforms thereof, is not completely dissolved in the aqueous phase of thesuspension. In the process provided herein, the suspension comprisesabout 0.005 mg/mL to about 2.5 mg/mL, about 0.01 mg/mL to about 2.0mg/mL, about 0.01 mg/mL to about 1 mg/mL, about 0.01 mg/mL to about 0.5mg/mL, about 0.01 mg/mL to about 0.2 mg/mL, or about 0.015 mg/mL toabout 0.115 mg/mL of the compound of Formula (I) or a salt or amorphousor polymorph form thereof. In some embodiments, the suspension comprises0.015 mg/mL of the compound of Formula (I) including salts and amorphousand polymorph forms thereof. In some embodiments, the suspensioncomprises 0.035 mg/mL of the compound of Formula (I) including salts andamorphous and polymorph forms thereof. In some embodiments, thesuspension comprises 0.115 mg/mL of the compound of Formula (I)including salts and amorphous and polymorph forms thereof.

In some embodiments of the process provided herein, the aqueoussolution, the slurry, the suspension, or combination thereof, areprepared in tanks. For example, the tank can be a tank used formanufacturing. In some embodiments, the tank is a stainless steel tank.In some embodiments, the tanks are jacketed for steam. In someembodiments, the tanks are equipped with one or more mixers, forexample, a standard mixer and/or homogenizer, which are used to mix theingredients added to the tank. In some embodiments, the tank is equippedwith a heating and/or cooling device. In some embodiments, the tankscomprise ports for addition, recirculation equipment, transferequipment, mixers, heating and/or cooling equipment, and combinationsthereof. In some embodiments, the tanks have a capacity between about 5L and about 5000 L. In some embodiments, the tanks have a capacitybetween about 5 L and about 3000 L; about 5 L and about 2000 L; about 5L and about 1000 L; about 5 L and about 500 L; about 5 L and about 300L; about 5 L and about 150 L; about 5 L and about 100 L; about 5 L andabout 50 L; about 5 L and about 30 L; about 5 L and about 20 L; about 20L and about 5000 L; about 20 L and about 3000 L; about 20 L and about2000 L; about 20 L and about 1000 L; about 20 L and about 500 L; about20 L and about 300 L; about 20 L and about 150 L; about 20 L and about100 L; about 20 L and about 50 L; about 20 L and about 30 L; about 30 Land about 5000 L; about 30 L and about 3000 L; about 30 L and about 2000L; about 30 L and about 1000 L; about 30 L and about 500 L; about 30 Land about 300 L; about 30 L and about 150 L; about 30 L and about 100 L;about 30 L and about 50 L; about 50 L and about 5000 L; about 50 L andabout 3000 L; about 50 L and about 2000 L; about 50 L and about 1000 L;about 50 L and about 500 L; about 50 L and about 300 L; about 50 L andabout 150 L; about 50 L and about 100 L; about 100 L and about 5000 L;about 100 L and about 3000 L; about 100 L and about 2000 L; about 100 Land about 1000 L; about 100 L and about 500 L; about 100 L and about 300L; about 100 L and about 150 L; about 150 L and about 5000 L; about 150L and about 3000 L; about 150 L and about 2000 L; about 150 L and about1000 L; about 150 L and about 500 L; about 150 L and about 300 L; about300 L and about 5000 L; about 300 L and about 3000 L; about 300 L andabout 2000 L; about 300 L and about 1000 L; about 300 L and about 500 L;about 500 L and about 5000 L; about 500 L and about 3000 L; about 500 Land about 2000 L; about 500 L and about 1000 L; about 1000 L and about5000 L; about 1000 L and about 3000 L; about 1000 L and about 2000 L;about 2000 L and about 5000 L; about 2000 L and about 3000 L; or about3000 L and about 5000 L. In some embodiments, the tank has a capacity ofabout 5000 L, about 3000 L, about 2000 L, about 1000 L, about 500 L,about 300 L, about 150 L, about 100 L, about 50 L, about 30 L, about 20L, or about 5 L. Other size tanks are known and can be used with theprovided process.

In some embodiments, the process is performed using a scaled-upmanufacturing process. A scaled-up manufacturing process can be used forvolumes greater than 1 L or about 1 L or greater than 1 gallon or about1 gallon, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, or moreliters.

In the process provided herein, the process comprises asepticallyfilling a container with the suspension to prepare a single-dose,ready-to-use formulation. Examples of containers include, but are notlimited to, vials, bottles, ampules, and syringes. In some embodiments,the suspension is aseptically filled into a single-use vial (i.e.,unused portions of each vial are discarded and not saved for lateradministration). In some embodiments, the vial is a plastic vial. Forexample, the vial can be made of polyethylene, polypropylene,polyolefins, polyethylene terephthalate, polyethylene terephthalate G,poly(vinyl chloride), and mixtures thereof. In some embodiments, thevial is a polypropylene vial. In some embodiments, the vial is a glassvial. The container can be any size that can fit the desired amount ofthe formulation. For example, the container can be a 1 mL, 2 mL, 3 mL, 4mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL container. In someembodiments, the container is a 3 mL vial. In some embodiments, thecontainer is a 5 mL vial. In some embodiments, the container is a 3 mLpolypropylene vial. For example, a polypropylene vial that is made usingblow-fill-seal technology. In some embodiments, the vial is designed foreasy withdrawal of the formulation with a syringe. In some embodiments,the vial has a Luer slip design. In some embodiments, the vial has aLuer lock design.

The resulting single-dose, ready-to-use formulations produced by theprocess provided herein are filled into containers comprising betweenabout 0.005 mg/mL and about 2.5 mg/mL of the compound of Formula (I),including amorphous and polymorph forms thereof, for example, betweenabout 0.005 mg/mL to about 2 mg/mL, about 0.01 mg/mL to about 1.8 mg/mL,about 0.015 mg/mL to about 0.115, about 0.025 mg/mL to about 1.6 mg/mL,about 0.05 mg/mL to about 1.5 mg/mL, about 0.075 mg/mL to about 1.25mg/mL, about 0.1 mg/mL to about 1 mg/mL, or about 0.25 mg/mL to about0.75 mg/mL. In some embodiments, the containers comprise a formulationcomprising about 0.015 mg/mL of the compound of Formula (I), includingamorphous and polymorph forms thereof. In some embodiments, thecontainers comprise a formulation comprising about 0.035 mg/mL of thecompound of Formula (I), including amorphous and polymorph formsthereof. In some embodiments, the containers comprise a formulationcomprising about 0.115 mg/mL of the compound of Formula (I), includingamorphous and polymorph forms thereof. In some embodiments, thecontainers comprise a concentration between about 0.1 mg/mL and 4 mg/mL.In some embodiments, the concentration is 2 mg/mL.

In some embodiments, the process further comprises terminallysterilizing the container containing the suspension. For example, thesterilization can be performed at 121.1° C. (250° F.) or at lowertemperatures, for example, between about 70-100° C., to achieve an F_(o)of NLT 2. In some embodiments, the NLT is greater than 10 or greaterthan 30. In some embodiments, the container is terminally sterilizedwhen the suspension comprises about 0.05 mg/mL to about 10 mg/mL of thecompound of Formula (I) or a salt or amorphous or polymorph formthereof. For example, the suspension comprises about 0.05 mg/mL to about5 mg/mL, about 0.05 mg/mL to about 2.5 mg/mL, about 0.05 mg/mL to about1 mg/mL, about 0.05 mg/mL to about 0.5 mg/mL, about 0.05 mg/mL to about0.1 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about 0.1 mg/mL to about 1mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about 0.1 mg/mL to about 0.25mg/mL, about 0.25 mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 5mg/mL, about 0.25 mg/mL to about 2.5 mg/mL, about 0.25 mg/mL to about 1mg/mL, about 0.25 mg/mL to about 0.5 mg/mL, bout 0.5 mg/mL to about 10mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 2.5mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 1 mg/mL to about 10mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 2.5 mg/mL,about 2.5 mg/mL to about 10 mg/mL, about 2.5 mg/mL to about 5 mg/mL, orabout 5 mg/mL to about 10 mg/mL of the compound of Formula (I) or a saltor amorphous or polymorph form thereof.

In some embodiments, the process further comprises labeling thecontainers. In some embodiments, the process further comprises packagingthe containers, for example, into boxes, cartons, or pre-formedblisters. In some embodiments, the process further comprises labelingthe boxes, cartons, or preformed blisters.

3. Single-Dose, Ready-to-Use Formulations

Provided herein are single-dose, ready-to-use pharmaceuticalformulations comprising a compound of Formula (I), includingpharmaceutically acceptable salts and amorphous and polymorph formsthereof, prepared by the process described herein. In some embodiments,the formulations are prepared as single-dose formulations. Providedherein are pharmaceutical formulations prepared from a polymorph form ofa compound of Formula (I). In some embodiments, the polymorph form isForm 1. In some embodiments, the polymorph form is a mixture of Form 1and Form 9. In some embodiments, the polymorph is a non-stoichiometricor stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulation comprises a polymorph form of a compound of Formula (I). Insome embodiments, the polymorph form is Form 1. In some embodiments, thepharmaceutical formulation comprises a polymorph form of a compound ofFormula (I) that is a mixture of forms. In some embodiments, the mixtureof forms is a mixture of Forms 1 and 9. In some embodiments, thepharmaceutical formulation comprises a polymorph form of a compound ofFormula (I) that is a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein contains polymorphForm 1 that has a purity of at least about 90% (not including water orsolvents). In some embodiments, the purity is at least about 95%. Insome embodiments, the purity is at least about 98%. For example, thepurity is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the formulation comprising Form 1 is substantially free of other formsof the compound of Formula (I), e.g., Form 9. In some embodiments, theformulation contains less than 15% by weight of other forms of thecompound of Formula (I), such as less than 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of other forms ofthe compound of Formula (I). In some embodiments, the other forms of thecompound of Formula (I) are other anhydrous forms of the compound ofFormula (I). In some embodiments, the formulation contains less thanabout 15% by weight of one or more other compounds of Formula (I). Forexample, the formulation contains less than 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of one or more otherforms of the compound of Formula (I). For example, the formulation cancontain less than about 15% by weight of Form 2, Form 3, Form 4, Form 5,Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, a non-stoichiometricor stoichiometric hydrate of Form 1, or combinations of two or morethereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein contains anon-stoichiometric or stoichiometric hydrate of polymorph Form 1 havingbetween 1% and about 20% by weight water that has a purity of at leastabout 90%. In some embodiments, the purity is at least about 95%. Insome embodiments, the purity is at least about 98%. For example, thepurity is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the formulation comprising the non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water issubstantially free of other forms of the compound of Formula (I), e.g.,Form 9. In some embodiments, the formulation contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%,0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% byweight of other forms of the compound of Formula (I). In someembodiments, the other forms of the compound of Formula (I) are otheranhydrous forms of the compound of Formula (I). In some embodiments, theformulation contains less than about 15% by weight of one or more othercompounds of Formula (I). For example, the formulation contains lessthan 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%,0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001%by weight of one or more other forms of the compound of Formula (I). Forexample, the formulation can contain less than about 15% by weight ofForm 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9,Form 10, Form 11, or combinations of two or more thereof.

In some embodiments, the single-dose, ready-to-use formulation preparedby the process provided herein comprises about 0.001 mg to about 5.0 mgper injection of a compound of Formula (I), including amorphous andpolymorph forms thereof. For example, the formulation in someembodiments comprises about 0.001 mg to about 4 mg, about 0.001 mg toabout 3 mg, about 0.001 mg to about 2 mg, about 0.001 mg to about 1 mg,about 0.001 mg to about 0.5 mg, 0.001 mg to about 0.4 mg, about 0.001 mgto about 0.3 mg, about 0.001 mg to about 0.25 mg, about 0.001 mg toabout 0.2 mg, about 0.001 mg to about 0.15 mg, about 0.001 mg to about0.1 mg, about 0.001 mg to about 0.075 mg, about 0.001 mg to about 0.055mg, about 0.001 mg to about 0.05 mg, about 0.001 mg to about 0.035 mg,about 0.001 mg to about 0.025 mg, about 0.001 mg to about 0.01 mg, about0.001 mg to about 0.005 mg, about 0.005 mg to about 5.0 mg, about 0.0075mg to about 5.0 mg, about 0.01 mg to about 5.0 mg, about 0.01 mg toabout 4.0 mg, about 0.01 mg to about 3.0 mg, about 0.01 mg to about 2.0mg, about 0.01 mg to about 1.0 mg, about 0.01 mg to about 0.7 mg, about0.01 mg to about 0.5 mg, about 0.01 mg to about 0.3 mg, about 0.01 mg toabout 0.23 mg, about 0.01 mg to about 0.1 mg, about 0.01 mg to about0.07 mg, about 0.01 mg to about 0.05 mg, about 0.01 mg to about 0.03 mg,about 0.03 mg to about 4.0 mg, about 0.03 mg to about 3.0 mg, about 0.03mg to about 2.0 mg, about 0.03 mg to about 1.0 mg, about 0.03 mg toabout 0.7 mg, about 0.03 mg to about 0.5 mg, about 0.03 mg to about 0.3mg, about 0.03 mg to about 0.23 mg, about 0.03 mg to about 0.1 mg, about0.03 mg to about 0.07 mg, about 0.03 mg to about 0.05 mg, about 0.07 mgto about 4.0 mg, about 0.07 mg to about 3.0 mg, about 0.07 mg to about2.0 mg, about 0.07 mg to about 1.0 mg, about 0.07 mg to about 0.7 mg,about 0.07 mg to about 0.5 mg, about 0.07 mg to about 0.3 mg, about 0.07mg to about 0.23 mg, about 0.07 mg to about 0.1 mg, about 0.025 mg toabout 5.0 mg, about 0.045 mg to about 5.0 mg, about 0.05 mg to about 5.0mg, about 0.075 mg to about 5.0 mg, about 0.1 mg to about 5.0 mg, about0.25 mg to about 5.0 mg, about 0.01 mg to about 3.0 mg, about 0.025 mgto about 2.0 mg, about 0.01 mg to about 0.1 mg, and about 0.15 mg toabout 0.25 mg of the compound of Formula (I), including amorphous andpolymorph forms thereof. In some embodiments, the formulation comprisesabout 0.001 mg, 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.07 mg, 0.1 mg,0.23 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.2 mg, 1.5 mg, 1.7 mg, 2.0mg, 2.2 mg, 2.5 mg, 2.7 mg, 3.0 mg, 3.2 mg, 3.5 mg, 3.7 mg, 4.0 mg, 4.2mg, 4.5 mg, 4.7 mg, or 5.0 mg of the compound of Formula (I), includingamorphous and polymorph forms thereof. In some embodiments, thesingle-dose, ready-to-use formulation comprises 0.03 mg of the compoundof Formula (I), including amorphous and polymorph forms thereof. In someembodiments, the single-dose, ready-to-use formulation comprises 0.07 mgof the compound of Formula (I), including amorphous and polymorph formsthereof. In some embodiments, the single-dose, ready-to-use formulationcomprises 0.115 mg of the compound of Formula (I), including amorphousand polymorph forms thereof.

The single-dose, ready-to-use formulations prepared by the processprovided herein comprising a compound of Formula (I), including saltsand amorphous and polymorph forms thereof, can comprise a conventionalpharmaceutical carrier, excipient, or the like. In some embodiments, thecompounds of Formula (I), including salts and amorphous and polymorphforms thereof, are formulated as a suspension. For example, the compoundof Formula (I) is not completely dissolved in the pharmaceuticallyacceptable carrier, i.e., the compound of Formula (I) is suspended inthe pharmaceutically acceptable carrier. In some embodiments, theformulation comprises the compound of Formula (I) suspended in apharmaceutically acceptable carrier. In some embodiments, theformulation comprises a polymorph form of Formula (I) suspended in apharmaceutically acceptable carrier. In some embodiments, theformulation comprises Form 1 suspended in a pharmaceutically acceptablecarrier. In some embodiments, the formulation comprises anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water suspended in a pharmaceutically acceptablecarrier. In some embodiments, the pharmaceutical formulation is asolution, i.e., the compound of Formula (I) is completely dissolved inthe pharmaceutically acceptable carrier.

In some embodiments, the polymorph form is dried prior to mixing withthe pharmaceutically acceptable carrier.

In some embodiments, the single-dose, ready-to-use pharmaceuticallyadministrable formulations comprising a compound of Formula (I),including amorphous and polymorph forms thereof, can optionally comprisepharmaceutical excipients in a carrier, e.g., water, saline, buffer,aqueous dextrose, mannitol, glycerol, glycols, ethanol or the like, toform a suspension. If desired, the pharmaceutical formulation can alsocontain minor amounts of nontoxic auxiliary substances such as wettingagents, emulsifying agents, co-solvents, solubilizing agents, pHbuffering agents, and the like.

In some embodiments, a single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises water.Suitable types of water include, but are not limited to, deionizedwater, distilled water, reverse osmosis filtered water, reagent gradewater, water for injection (WFI), USP/EP grade water suitable for use inpharmaceuticals, and aqueous buffer solutions. The water issubstantially free of contaminants, such as parasites, pathogens,chemical contaminants, and particulate contamination. For example, thepharmaceutical formulation can include an aqueous buffer solution.Examples of buffer agents include, but are not limited to, acetic acid,acetic anhydride, adipic acid, alanine, albumin, alcohol, alfadex,ammonia, ammonium acetate, ammonium sulfate, anhydrous citric acid,anhydrous dextrose, anhydrous lactose, anhydrous trisodium citrate,arginine, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoicacid, calcium chloride, calcium gluceptate, calcium hydroxide, calcium,caprylic acid, carbon dioxide, citric acid monohydrate, dibasicpotassium phosphate, diethanolamine, disodium citrate sesquihydrate,disodium hydrogen citrate, edetate calcium disodium, edetate disodium,edetate sodium, edetic acid, ethanolamine hydrochloride, ferricchloride, gluceptate sodium, glycine hydrochloride, glycine, guanidinehydrochloride, histidine, hydrochloric acid, isoleucine, lactic acid,lactobionic acid, leucine, lysine acetate, lysine, lysine monohydrate,magnesium chloride, magnesium stearate, maleic acid, metaphosphoricacid, methanesulfonic acid, nitric acid, phosphate ion, phosphoric acid,potassium chloride, potassium hydroxide, potassium phosphate(monobasic), sodium acetate, sodium ascorbate, sodium benzoate, sodiumbicarbonate, sodium bisulfate, sodium carbonate, sodium citrate, sodiumhydroxide, sodium hypochlorite, sodium phosphate dihydrate, sodiumphosphate, sodium phosphate p-32, sodium phosphate dibasic dihydrate,sodium phosphate dibasic dodecahydrate, sodium phosphate dibasic, sodiumphosphate dibasic (anhydrous), sodium phosphate dibasic heptahydrate,sodium phosphate monobasic (anhydrous), sodium phosphate monobasicdihydrate, sodium phosphate monobasic monohydrate, sodium phosphatemonobasic, sodium sulfate (anhydrous), sodium sulfate, sodiumthioglycolate, sodium thiomalate, sodium thiosulfate, succinic acid,sulfuric acid, tartaric acid, tartaric acid (dl), trifluoroacetic acid,tromantadine, and tromethamine. In some embodiments, the pharmaceuticalformulation comprises phosphate buffered saline.

In some embodiments, a single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises aviscosity enhancer. The viscosity enhancer can be, for example, acellulose or cellulose derivative or a synthetic polymer. Examples ofviscosity enhancers include, but are not limited to, microcrystallinecellulose (Avicel: Asahi Kasei Corp., etc.), microcrystalline cellulosecarmellose sodium (Avicel RC: Asahi Kasei Corp., etc.), methyl cellulose(Metolose SM: Shin-Etsu Chemical Co., Ltd., etc.), ethyl cellulose(Ethocel: Dow Chemical Co., etc.), hydroxypropyl cellulose (Nisso HPC:Nippon Soda Co., Ltd., etc.), low-substituted hydroxypropyl cellulose(L-HPC: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2208 (Metolose 90SH: Shin-Etsu Chemical Co., Ltd., etc.),hydroxypropyl methyl cellulose 2906 (Metolose 65SH: Shin-Etsu ChemicalCo., Ltd., etc.), hydroxypropyl methyl cellulose 2910 (Metolose 60SH:Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl cellulose phthalate200731 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropylcellulose phthalate 220824 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.),hydroxypropyl methyl cellulose acetate succinate (Shin-Etsu AQOAT:Shin-Etsu Chemical Co., Ltd., etc.), carmellose (NS-300: Gotoku ChemicalCo., Ltd., etc.), carmellose calcium (ECG-505: Gotoku Chemical Co.,Ltd., etc.), carmellose sodium (Cellogen: Daiichi Kogyo Seiyaku Co.,Ltd., etc.), croscarmellose sodium (Ac-Di-Sol: Asahi Kasei Corp., etc.),carboxymethyl ethyl cellulose (CMEC: Freund Corp., etc.), celluloseacetate phthalate (CAP: Wako Pure Chemical Industries, Ltd., etc.),hydroxyethyl cellulose (NATROSOL: Aqualon Corp., etc.), polyvinylalcohol, polyvinylpyrrolidone, or mixtures thereof. In some embodiments,the viscosity enhancer is a cellulose derivative. In some embodiments,the cellulose derivative is a water-soluble cellulose or water-solublecellulose derivative. In some embodiments, a cellulose derivative is acarboxymethylcellulose, or a pharmaceutically acceptable salt thereof.For example, a cellulose derivative is sodium carboxymethylcellulose. Aviscosity enhancer can be present in the formulation in an amount ofabout 0.1% to about 5% by weight of the formulation. For example, about0.1% to about 2.5%; about 0.1% to about 1%; about 0.1% to about 0.75%;about 0.1% to about 0.5%; about 0.1% to about 0.25%; about 0.25% toabout 5%; about 0.5% to about 5%; about 1% to about 5%; about 2.5% toabout 5%; about 0.25% to about 0.75%; about 0.5% to about 1%; and about1% to about 2% by weight of the formulation. In some embodiments, theviscosity enhancer can be present in the formulation at about 0.5% byweight of the formulation. In some embodiments, the viscosity enhanceris a cellulose derivative and is present in the formulation at about0.5% by weight of the formulation.

In some embodiments, a single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises asurfactant. Non-limiting examples of surfactants include polysorbatessuch as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,and polysorbate 85; polyoxyethylene hydrogenated castor oils such aspolyoxyethylene hydrogenated castor oil 60 and polyoxyl 35 castor oil;sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylenepolyoxypropylene glycols; polyoxyethylene fatty acid ethers; polyoxylstearates; phosphatidylcholines; phosphatidylglycerols, including, butnot limited to phosphatidylglycerols containing fatty acids, fattyalcohols, or a combination thereof, and carbon chain lengths between 4and 20 carbons; and other surfactants, including, but not limited to,1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)),1,2-dioleoyl-sn-glycero-3-phosphocholine,1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)),1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-phosphocholine, deoxycholic acid,dipalmitoylphosphatidylglycerol (dl), distearoylphosphatidylcholine(dl), docusate sodium, egg phospholipids, glyceryl palmitostearate,glyceryl trioleate, hydrogenated soybean lecithin, hydrolyzed soyprotein (enzymatic; 2000 mw), hydroxyethylpiperazine ethane sulfonicacid, lecithin, miripirium chloride, n-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, oleic acid, palmiticacid, peg vegetable oil, peg-20 sorbitan isostearate, peg-40 castor oil,phospholipid, poloxamer 188, polyethylene glycol 200, polyethyleneglycol 300, polyethylene glycol 3350, polyethylene glycol 400,polyethylene glycol 4000, polyethylene glycol 600, polyoxyethylene fattyacid esters, sodium cholesteryl sulfate, sodium deoxycholate, sodiumn-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glyc,sodium oleate, sorbitan monolaurate, sorbitan monopalmitate, stearicacid, tricaprylin, or mixtures thereof. In some embodiments, thesurfactant is a polysorbate. For example, the pharmaceutical formulationcomprises polysorbate 80. A surfactant can be present in the formulationin an amount of about 0.001% to about 0.5% by weight of the formulation.In some embodiments, the concentration of surfactant depends on thecritical micelle concentration of the individual surfactant. In someembodiments, the amount of surfactant is enough to be above the criticalmicelle concentration of the surfactant, enough to coat the surface areaof the particles, or both. For example, about 0.001% to about 0.25%;about 0.001% to about 0.1%; about 0.001% to about 0.075%; about 0.001%to about 0.05%; about 0.001% to about 0.025%; about 0.0025% to about0.5%; about 0.005% to about 0.5%; about 0.1% to about 0.5%; about 0.01%to about 0.5%; about 0.01% to about 0.25%; about 0.01% to about 0.1%;about 0.01% to about 0.075%; about 0.01% to about 0.05%; about 0.01% toabout 0.025%; about 0.025% to about 0.5%; about 0.05% to about 0.5%;about 0.1% to about 0.5%; about 0.025% to about 0.5%; about 0.025% toabout 2.5%; about 0.025% to about 0.075%; about 0.05% to about 2.5%;about 0.05% to about 0.1%; and about 0.1% to about 0.2% by weight of theformulation. In some embodiments, the surfactant can be present in theformulation at about 0.05% by weight of the formulation.

In some embodiments, a single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises a compoundof Formula (I), including amorphous and polymorph forms thereof, and apharmaceutically acceptable carrier. For example, the formulationcomprises a compound of Formula (I) and saline, e.g., phosphate bufferedsaline. In some embodiments, the pharmaceutical formulation comprises acompound of Formula (I), a pharmaceutically acceptable carrier, and oneor more excipients. For example, the formulation comprises a compound ofFormula (I), a pharmaceutically acceptable carrier, e.g., phosphatebuffered saline, and one or more excipients, e.g., a surfactant and acellulose derivative. In some embodiments, the surfactant is apolysorbate, e.g., polysorbate 80. In some embodiments, the cellulosederivative is sodium carboxymethylcellulose. In some embodiments, thepharmaceutical formulation comprises a compound of Formula (I), e.g., apolymorph form of Formula (I), e.g., Form 1, a pharmaceuticallyacceptable carrier, e.g., phosphate buffered saline, and one or moreexcipients, e.g., sodium carboxymethylcellulose and a polysorbate, e.g.,polysorbate 80.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises a compoundof Formula (I), e.g., a polymorph form of Formula (I), about 0.01% toabout 5% by weight of a cellulose derivative, and about 0.01% to about0.5% by weight of a surfactant in an aqueous buffer. For example, apharmaceutical formulation provided herein can include a compound ofFormula (I), e.g., Form 1 or a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water, about0.5% by weight sodium carboxymethylcellulose and about 0.05% by weightpolysorbate 80 in phosphate buffered saline.

In some embodiments, a single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein has a pH of about6.0 to about 8.0. For example, a pharmaceutical formulation can have apH of about 7.3 or 7.4. In some embodiments a pharmaceutical formulationprovided herein has a pH of about 3.0 to about 5.0. For example, apharmaceutical formulation can have a pH of about 3.8.

The single-dose, ready-to-use pharmaceutical formulations prepared bythe process provided herein can contain an excipient. The term“excipient” is used herein to describe any ingredient other than thecompound(s) provided herein, e.g., compound of Formula (I), includingpolymorph and amorphous forms thereof. Pharmaceutically acceptableexcipients include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, self-emulsifying drug delivery systems(SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens,poloxamers or other similar polymeric delivery matrices, serum proteins,such as human serum albumin, buffer substances such as phosphates, tris,glycine, sorbic acid, potassium sorbate, partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes, such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium-chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, cellulose-based substances,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates,waxes, polyethylene-polyoxypropylene-block polymers, and wool fat,solubilizers, tonicity agents, stabilizers, preservatives, saltformation substances, chelators/chelating agents, viscosity enhancers,contrast agent, anti-foam agents, control release agents, lubricants,adhesives, analgesics, antiheparins, antivirals, colorants, emollients,propellants, and other excipients, including, but not limited toactivated charcoal, barium sulfate, bibapcitide, brocrinat, calcobutrol,glutathione, zinc, zinc acetate, zinc carbonate, zinc chloride, and zincoxide. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives canalso be advantageously used to enhance delivery of compounds describedherein. Dosage forms or formulations containing a compound as describedherein in the range of 0.005% to 100% with the balance made up fromnon-toxic carrier may be prepared. The contemplated formulations cancontain 0.001%-100% active ingredient, in one embodiment 0.1-95%, inanother embodiment 75-85%, in a further embodiment 20-80%. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in the art; for example, see Remington: The Science andPractice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain asolubilizer. Examples of solubilizers include, but are not limited to,acetyltryptophan (dl), alanine, albumin (aggregated), alcohol, alfadexintracavitary powder, ammonia, anhydrous dextrose, anhydrous lactose,anhydrous trisodium citrate, arginine, ascorbic acid, aspartic acid,benzenesulfonic acid, benzyl alcohol, benzyl benzoate, benzyl chloride,betadex sulfobutyl ether sodium, butanol (mixed isomers), caprylic acid,carboxymethylcellulose, carboxymethylcellulose sodium, castor oil,cholesterol, corn oil, cottonseed oil, creatine, creatinine,croscarmellose sodium, crospovidone, cysteine hydrochloride, cysteine,cysteine (dl), dextran 40, dextran, diacetylated monoglycerides,diethanolamine, dimethyl sulfoxide, ethanolamine hydrochloride, ethylacetate, ethylene-vinyl acetate copolymer (15% vinyl acetate), gammacyclodextrin, gelatin, gentisic acid ethanolamide, gentisic acid,gluconolactone, glucuronic acid, glycerin, hetastarch, human albuminmicrospheres, hyaluronate sodium, hydroxypropyl betadex intramuscularinjection, hypromellose, isopropyl alcohol, methylcellulose,methylpyrrolidone, microcrystalline cellulose, N,N-dimethylacetamide,niacinamide, oleic acid, palmitic acid, peanut oil, peg vegetable oil,peg-20 sorbitan isostearate, peg-40 castor oil, phenylethyl alcohol,polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol3350, polyethylene glycol 400, polyethylene glycol 4000, polyethyleneglycol 600, polypropylene glycol, polyvinyl alcohol, poppy seed oil,povidone k12, povidone k17, povidone, proline, propyl gallate, propyleneglycol, sesame oil, soybean oil, starch, stearic acid, trimethylsilyltreated dimethiconol/trimethylsiloxysilicate crosspolymer, and yellowwax, and combinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a tonicityagent. Examples of tonicity agents include, but are not limited to,dextrose monohydrate, dextrose solution, dextrose, dimethyl sulfoxide,fructose, gluconolactone, glucuronic acid, glycerin, glycinehydrochloride, glycine, guanidine hydrochloride, histidine, hydrochloricacid, hypertonic sodium chloride solution, isoleucine, isopropylalcohol, isotonic sodium chloride solution, lactic acid (dl),lactobionic acid, lactose monohydrate, lactose, leucine, lysine acetate,lysine, lysine monohydrate, magnesium chloride, magnesium stearate,maleic acid, mannitol, meglumine, methionine, methylboronic acid,polypropylene glycol, potassium chloride, potassium hydroxide, potassiumphosphate (monobasic), proline, propyl gallate, propylene glycol,saccharin sodium, serine, sodium acetate, sodium ascorbate, sodiumbenzoate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodiumchloride, sodium citrate, sodium gluconate, sodium hydroxide, sodiumhypochlorite, sodium lactate, sodium phosphate dihydrate, sodiumphosphate, sodium phosphate p-32, sodium phosphate dibasic dihydrate,sodium phosphate dibasic dodecahydrate, sodium phosphate dibasic, sodiumphosphate dibasic (anhydrous), sodium phosphate dibasic heptahydrate,sodium phosphate monobasic (anhydrous), sodium phosphate monobasicdihydrate, sodium phosphate monobasic monohydrate, sodium phosphatemonobasic, sodium sulfate (anhydrous), sodium sulfate, sodiumthioglycolate, sodium thiomalate, sodium thiosulfate, sorbitol, succinicacid, sucrose, sulfuric acid, tartaric acid, tartaric acid (dl),threonine, trehalose, trifluoroacetic acid, trisodium citrate dihydrate,tromethamine, tryptophan, tyrosine, urea, urethane, and valine andcombinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain astabilizer. Examples of stabilizers include, but are not limited to,acetyltryptophan (dl), alanine, albumin (aggregated), alcohol, alfadexintracavitary powder, ammonia, anhydrous dextrose, anhydrous lactose,anhydrous trisodium citrate, arginine, ascorbic acid, aspartic acid,benzenesulfonic acid, benzyl alcohol, benzyl benzoate, benzyl chloride,betadex sulfobutyl ether sodium, boric acid, butanol (mixed isomers),caprylic acid, carboxymethylcellulose, carboxymethylcellulose sodium,castor oil, cholesterol, creatine, creatinine, croscarmellose sodium,crospovidone, cysteine hydrochloride, cysteine, cysteine (dl), dextran40, dextran, ethylene-vinyl acetate copolymer (15% vinyl acetate),gelatin, gentisic acid ethanolamide, gentisic acid, hetastarch, humanalbumin microspheres, hyaluronate sodium, hypromellose, meglumine,methionine, methylboronic acid, methylcellulose, methylpyrrolidone,microcrystalline cellulose, miripirium chloride,n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, N,N-dimethylacetamide, niacinamide,phenylalanine, polyvinyl alcohol, povidone K12, povidone K17, povidone,serine, sodium citrate, sodium gluconate, sodium lactate, starch,threonine, trehalose, tricaprylin, trimethylsilyl treateddimethiconol/trimethylsiloxysilicate crosspolymer, trisodium citratedihydrate, tryptophan, tyrosine, urea, and valine and combinationsthereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain apreservative. Examples of preservatives include, but are not limited to,acetone sodium bisulfite, alpha-tocopherol, benzalkonium chloride,benzyl alcohol, benzyl benzoate, benzyl chloride, boric acid, butylatedhydroxyanisole, butylated hydroxytoluene, butylparaben, chlorobutanol,chlorobutanol hemihydrate, cresol, diethyl pyrocarbonate, edetatecalcium disodium, edetate disodium, edetate sodium, edetic acid,hexylresorcinol, metacresol, methylparaben, miripirium chloride,monothioglycerol, nitrogen, phenol, phenylethyl alcohol, phenylmercuricnitrate, potassium bisulfite, potassium metabisulfite, propylparaben,sodium ascorbate, sodium benzoate, sodium bisulfate, sodium chlorate,sodium dithionite, sodium formaldehyde sulfoxylate, sodium iodide,sodium metabisulfite, sodium sulfite, sodium tartrate, sulfur dioxide,sulfurous acid, and thimerosal and combinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a saltformation agent. Examples of salt formation agents include, but are notlimited to, acetic acid, acetic anhydride, adipic acid, ammoniumacetate, ammonium sulfate, anhydrous citric acid, benzoic acid, calciumchloride, calcium gluceptate, calcium hydroxide, calcium, carbondioxide, citric acid monohydrate, dibasic potassium phosphate,diethanolamine, disodium citrate sesquihydrate, disodium hydrogencitrate, hydrochloric acid, isoleucine, lactic acid (dl), lactobionicacid, magnesium chloride, magnesium stearate, maleic acid,metaphosphoric acid, methanesulfonic acid, nitric acid, phosphate ion,phosphoric acid, sodium hydroxide, sodium hypochlorite, sodium phosphatedihydrate, sodium phosphate, sodium phosphate p-32, sodium phosphatedibasic dihydrate, sodium phosphate dibasic dodecahydrate, sodiumphosphate dibasic, sodium phosphate dibasic (anhydrous), sodiumphosphate dibasic heptahydrate, sodium phosphate monobasic (anhydrous),sodium phosphate monobasic dihydrate, sodium phosphate monobasicmonohydrate, sodium phosphate monobasic, and trifluoroacetic acid andcombinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a chelatoror chelating agent. Examples of chelators or chelating agents include,but are not limited to, caldiamide sodium, caloxetate trisodium,calteridol calcium, edetate calcium disodium, edetate disodium, edetatesodium, edetic acid, ferric chloride, gluceptate sodium, methylboronicacid, nioxime, oxidronate disodium, peg-60 hydrogenated castor oil,pentasodium pentetate, pentetate calcium trisodium, pentetic acid,sodium phosphite, sodium pyrophosphate, sodium succinate hexahydrate,sodium trimetaphosphate, succimer, and versetamide and combinationsthereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a viscosityenhancer. Examples of viscosity enhancers include, but are not limitedto, carboxymethylcellulose, carboxymethylcellulose sodium,croscarmellose sodium, crospovidone, ethylene-vinyl acetate copolymer(15% vinyl acetate), gelatin, hetastarch, human albumin microspheres,hyaluronate sodium, hypromellose, methylcellulose, methylpyrrolidone,microcrystalline cellulose, polyvinyl alcohol, povidone K12, povidoneK17, povidone, starch, and trimethylsilyl treateddimethiconol/trimethylsiloxysilicate crosspolymer and combinationsthereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a contrastagent. Examples of contrast agents include, but are not limited to,diatrizoic acid, perflutren, stannous chloride, stannous fluoride,stannous tartrate, tetrakis(2-methoxyisobutylisocyanide)copper(I)tetrafluoroborate, and tetrofosmin and combinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain ananti-foam agent. Examples of anti-foam agents include, but are notlimited to, dimethicone, polysiloxane, silicone, and simethicone andcombinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a controlrelease agent. Examples of control release agents include, but are notlimited to, poly(dl-lactic-co-glycolic acid), (50:50; 12000 mw),polyglactin, and polylactide and combinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain alubricant. Examples of lubricants include, but are not limited to,silicone and simethicone and combinations thereof.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain anadhesive. An example of an adhesive includes, but is not limited to,Duro-Tak 87-2287.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain ananalgesic. An example of an analgesic includes, but is not limited to,disodium sulfosalicylate.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain ananti-heparin agent. An example of an anti-heparin agent includes, but isnot limited to, protamine sulfate.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain anantiviral agent. An example of an antiviral agent includes, but is notlimited to, tromantadine.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain a colorant.An example of a colorant includes, but is not limited to, methyleneblue.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain anemollient. An example of an emollient includes, but is not limited to,urethane.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein contain apropellant. An example of a propellant includes, but is not limited to,dichlorodifluoromethane.

The formulations prepared by the process provided herein aresingle-dose, ready-to-use pharmaceutical formulations packaged in acontainer for parenteral administration (injection or infusion). Forexample, the pharmaceutical formulation is prepared to contain thetherapeutically effective amount of the compound of Formula (I),including amorphous and polymorph forms thereof, and is intended to beused in a single subject for a single fusion or injection. Theformulations provided herein are not designed for multiple-doseadministration or for multiple use. The formulations provided herein are“ready-to-use,” i.e., formulations that do not require constitution ordilution with a prescribed amount of diluent, e.g., water for injectionor other suitable diluent, before use by the designated route. Forexample, a formulation in a vial, of the desired concentration, thatonly needs to be drawn up into a syringe.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises a volumeof about 0.1 mL to about 10 mL per container (i.e., per injection). Forexample, about 0.1 mL to about 10 mL, about 0.1 mL to about 5 mL, about0.1 mL to about 4 mL, about 0.1 mL to about 3 mL, about 0.1 mL to about2 mL, about 0.1 mL to about 1 mL, about 0.1 mL to about 0.5 mL, about0.1 mL to about 0.25 mL, about 2 mL to about 10 mL, about 2 mL to about5 mL, about 2 mL to about 4 mL, about 2 mL to about 3 mL, about 3 mL toabout 5 mL, about 3 mL to about 10 mL, about 0.5 mL to about 1 mL, about0.25 mL to about 2 mL. In some embodiments, the single-dose,ready-to-use pharmaceutical formulation prepared by the process providedherein comprises a volume of about 1 mL to about 10 mL per container(i.e., per injection). For example, about 1 mL to about 10 mL, about 1mL to about 5 mL, about 1 mL to about 4 mL, about 1 mL to about 3 mL,about 1 mL to about 2 mL, about 2 mL to about 10 mL, about 2 mL to about5 mL, about 2 mL to about 4 mL, about 2 mL to about 3 mL, about 3 mL toabout 5 mL, about 3 mL to about 10 mL. In some embodiments, theformulation comprises a volume of about 2 mL per container (i.e.,injection).

In some embodiments, the unit dosage of the compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.1 μg/kg toabout 10 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.1 μg/kg toabout 5 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.2 μg/kg toabout 9 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.25 μg/kg toabout 8 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.3 μg/kg toabout 7 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.4 μg/kg toabout 6 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.5 μg/kg toabout 5 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 0.6 μg/kg toabout 5 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 1.0 μg/kg toabout 4 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 2.0 μg/kg toabout 4 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 3.0 μg/kg toabout 5 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 4.0 μg/kg toabout 6 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is about 5.0 μg/kg toabout 10 μg/kg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.001 mg to 1 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.001 mg to 0.5 mgof body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.001 mg to 0.3 mgin humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.01 mg to 1 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.01 mg to 0.5 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.01 mg to 0.3 mg inhumans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.03 mg to 0.9 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.03 mg to 0.23 mgof body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.05 mg to 0.8 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.07 mg to 0.7 mg ofbody weight in humans.

In some embodiments, the unit dosage of compounds of Formula (I),including amorphous and polymorph forms thereof, is 0.08 mg to 0.7 mg ofbody weight in humans. In some embodiments, the unit dosage of compoundof Formula (I), including amorphous and polymorph forms thereof, is 0.1mg to 0.6 mg of body weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.12 mg to 0.6 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.14 mg to 0.5 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.16 mg to 0.5 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.18 mg to 0.4 mg ofbody weight in humans.

In some embodiments, the unit dosage of compound of Formula (I),including amorphous and polymorph forms thereof, is 0.2 mg to 0.4 mg ofbody weight in humans.

In some embodiments, the single-dose, ready-to-use pharmaceuticalformulations prepared by the process provided herein are stable for atleast 3 months. For example, the formulations do not exhibit a change(e.g., greater than 5%) in one or more of polymorph forms (e.g., anincrease or decrease of a certain form), appearance, pH, percentimpurities, activity (as measured by in vitro assays), or osmolarityover time, e.g., at least 3 months as compared to the originalformulation after manufacturing. In some embodiments, the single-dose,ready-to-use pharmaceutical formulations prepared by the processprovided herein are stable for at least 6 months. For example, theformulations do not exhibit a significant change (e.g., greater than 5%)in one or more of polymorph form (e.g., an increase or decrease of acertain form), appearance, pH, percent impurities, activity (as measuredby in vitro assays), or osmolarity over time, e.g., at least 6 months ascompared to the original formulation after manufacturing. In someembodiments, the single-dose, ready-to-use pharmaceutical formulationsprepared by the process provided herein are stable for at least 9months. For example, the formulations do not exhibit a significantchange (e.g., greater than 5%) in one or more of polymorph form (e.g.,an increase or decrease of a certain form), appearance, pH, percentimpurities, activity (as measured by in vitro assays), or osmolarityover time, e.g., at least 9 months as compared to the originalformulation after manufacturing. In some embodiments, the single-dose,ready-to-use pharmaceutical formulations prepared by the processprovided herein are stable for at least 12 months. For example, theformulations do not exhibit a significant change, as defined by theInternational Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH), in one or more ofpolymorph form (e.g., an increase or decrease of a certain form),appearance, pH, percent impurities, activity (as measured by in vitroassays), or osmolarity over time, e.g., at least 12 months as comparedto the original formulation after manufacturing.

In some such embodiments, the single-dose, ready-to-use pharmaceuticalformulation prepared by the process provided herein comprises betweenabout 0.005 mg/mL and 2.5 mg/mL of the compound of Formula (I),including amorphous and polymorph forms thereof, for example, betweenabout 0.005 mg/mL to about 2 mg/mL, about 0.01 mg/mL to about 1.8 mg/mL,about 0.025 mg/mL to about 1.6 mg/mL, about 0.05 mg/mL to about 1.5mg/mL, about 0.075 mg/mL to about 1.25 mg/mL, about 0.1 mg/mL to about 1mg/mL, or about 0.25 mg/mL to about 0.75 mg/mL. In some suchembodiments, the pharmaceutical formulation comprises about 0.015 mg/mLto about 0.115 mg/mL of the compound of Formula (I), including amorphousand polymorph forms thereof. In some such embodiments, thepharmaceutical formulation comprises about 0.015 mg/mL of the compoundof Formula (I), including amorphous and polymorph forms thereof. In somesuch embodiments, the pharmaceutical formulation comprises about 0.035mg/mL of the compound of Formula (I), including amorphous and polymorphforms thereof. In some such embodiments, the pharmaceutical formulationcomprises about 0.115 mg/mL of the compound of Formula (I), includingamorphous and polymorph forms thereof. In some embodiments, theinjection volume comprises between about 0.1 mg/mL and 4 mg/mL. In someembodiments, the injection volume is 2 mg/mL.

The single-dose, ready-to-use formulations prepared by the processprovided herein comprising a compound of Formula (I), includingamorphous and polymorph forms thereof, can be formulated as a pluralityof particles. For example, particles of a compound of Formula (I),including amorphous and polymorph forms thereof, can have a medianparticle size of less than 20 μm (e.g., less than about 15 μm; less thanabout 10 μm; less than about 7.5 μm; less than about 5 μm; less thanabout 2.5 μm; less than about 1 μm; and less than about 0.5 μm). Forexample, the median particle size can be between about 0.1 μm and 20 μm,such as between about 0.5-20, 0.5-15, 0.5-10, 0.5-7.5, 0.5-5, 0.5-2.5,0.5-1, 2.5-15, 5-10, 7.5-20, or 1-5 μm. In some embodiments, theparticles also comprise a polymer. Examples of suitable polymers includebiocompatible and biodegradable polymers like poly(lactic acid), apoly(glycolic acid), a poly(lactic-co-glycolic acid), apoly(lactide-co-glycolide), and mixtures thereof. In some embodiments,the particles comprise poly(lactic-co-glycolic acid) (PLGA).

In some embodiments, the compound of Formula (I), including amorphousand polymorph forms thereof, e.g., a polymorph form of Formula (I),e.g., Form 1, has a particle size distribution (D value), e.g., a D50,of between about 1 and about 6 μm, such as between about 1.5 and about 5μm, or about 2.4 to about 2.55 μm. For example, the D50 can be about1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3, 3.1, 3.2, 3.3, 3.4, 3.5, 4, 4.5, or 5 μm. In some embodiments, theD50 value is about 2.55 μm. In some embodiments, the D50 value is about2.45 μm. In some embodiments, the D50 value is about 2.1 μm. In someembodiments, the D50 value is about 2 μm. In some embodiments, the D50value is about 1.6 μm. The D50 can be measured by conventional particlesize measuring techniques well known to those skilled in the art. Suchtechniques include, for example, sedimentation field flow fractionation,photon correlation spectroscopy, light scattering, laser diffraction anddisc centrifugation.

In some embodiments, the single-dose, ready-to-use formulations preparedby the process provided herein comprising a compound of Formula (I),including amorphous and polymorph forms thereof, are administeredparenterally, including intramuscularly, intra-articularly,periarticularly, intraspinally, intradiscal, intrasynovially, andepidurally. In some embodiments, the formulation is administered to apatient with disc degeneration. In some embodiments, the formulation isadministered to a patient with osteoarthritis. In some embodiments, theformulation can be a bursa injection, a caudal injection (e.g., a caudalepidural steroid injection (ESI)), a facet injection, a facet synovialinjection, a hip joint injection, an intradiscal injection, an occipitalnerve injection, a sciatic/piriformis injection, a sacroiliac (SI) jointinjection, or combinations thereof. In some embodiments, the formulationcan be injected locally, for example, in a patient with osteoarthritis,at the site of osteoarthritis (e.g., knee, hip, shoulder, etc.).Injections can occur at one or more locations surrounding the joint. Insome embodiments, the injection is guided using an imaging method suchas ultrasound. In some embodiments, administration (e.g., injection) ofthe formulation is preceded or combined with a local anesthetic.

The single-dose, ready-to-use formulations prepared by the processprovided herein comprising a compound of Formula (I), includingamorphous and polymorph forms thereof, can also be administered incombination (administered together or sequentially) with other knownagents.

In some embodiments, the single-dose, ready-to-use formulations preparedby the process provided herein comprising a compound of Formula (I),including amorphous and polymorph forms thereof, can be administered incombination with one or more of the following: (a) Nonsteroidalanti-inflammatory drugs (NSAIDs), including, but not limited to,ibuprofen, naproxen, aspirin, acetaminophen, indomethacin (e.g.,INDOCIN® and TIVORBEX®), diclofenac by mouth or to the affected area(e.g., VOLTAREN®, ZIPSOR®, PENNSAID®, FLECTOR®, and CATAFLAM®),meloxicam (e.g., MOBIC), celecoxib (e.g., CELEBREX®), piroxicam (e.g.,FELDENE®), etodolac (e.g., LODINE®), nabumetone (e.g., RELAFEN®),lumiracoxib, valdecoxib (e.g., BEXTRA), etoricoxib, parecoxib,fenoprofen (e.g., NALFON®), oxaprozin (e.g., DAYPRO®), mefanamic acid(e.g. PONSTEL®), diflunisal (e.g., DOLOBID®), fenoprofen (e.g.,NALFON®), flurbirofen (e.g., ANSAID®), ketoprofen (e.g., ORUVAIL®),ketorolac (e.g., TORADOL®), sulindac (e.g., CLINORIL®), meclofenamate,choline salicylate-magnesium salicylate, salsalate (e.g., DISALCID®),and tolmetin (e.g., TOLECTIN®); (b) physical therapy; (c) injections ofcorticosteroid medications such as, e.g., prednisone, dexamethasone,hydrocortisone, and methylprenisolone; (d) injections of hyaluronic acidderivatives (e.g., HYALGAN®, SYNVISC®, EUFLEXXA®, GEL-ONE®, MONOVISC®,ORTHOVISC®, and SUPARTZ®); (e) injections or topical application ofCapsaicin (e.g., CAPSAGELL®); (f) narcotics, such as, e.g., codeine,fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone,and tramadol (e.g., ULTRAM®, CONZIP®, and RYZOLTL®); (g) antidepressantssuch as dulozetine (e.g., CYMBALTA®); (h) braces and/or shoe inserts orany device that can immobilize or support the joints to help keeppressure off it (e.g., splints, braces, shoe inserts or other medicaldevices); (i) realigning bones (osteotomy); (j) joint replacement(arthroplasty); and (k) chronic pain class.

In some embodiments, the single-dose, ready-to-use formulations preparedby the process provided herein comprising a compound of Formula (I),including amorphous and polymorph forms thereof, can be used to treatosteoarthritis. In some embodiments, the formulations can be used totreat osteoarthritis in combination with one or more of the followingdrugs or methods: prednisone, methylprednisolone, SYNVISC® (hylan G-F20), ABT-981 [MAbs (2015) 7(3):605-619], stem cell injection,JNJ-42160443 (fulranumab), platelet rich plasma (PRGF) injection,tanezumab, venlafaxine, PH-797804, PG-530742 (the dihydrated sodium saltPG-116800), Sprifermin (AS902330, rhFGF-18), epicutaneous ketoprofen intransfersome (IDEA-033) [Annals of the Rheumatic Diseases (2007)66(9):1178-1183], FX005 and FX006 (both by Flexion Therapeutics, Inc.),JNJ-39439335 (Mavatrep) [J. Med. Chem. (2015) 58(9):3859-3874],polmacoxib (Acelex, CG100649), balicatib (AAE581), GSK3196165,cebranopadol (GRT6005), fasinumab (REGN475), TPX-100 (by OrthoTrophix),PRX167700 (by Proximagen), EP 104IAR (extended release fluticasonepropionate composition), LY2951742 and LY545694 (both by Eli Lilly &Co), Adalimumab (Humira®), GW842166 (by GSK), YY1201 (by YooyoungPharmaceutical Co., Ltd.), CF101 (IB-MECA) and CF602 (both by Can-FiteBioPharma), PLA-695 (by Pfizer), VX-150 (by Vertex), ADL5859 and ADL5747(both by Adolor Corporation now Cubist Pharmaceuticals), funapide (INN)(TV-45070, XEN402), AGG-523 (by Pfizer) [Osteoarthritis Cartilage (2011)19(3):315-323], CNTX-4975 (capsaicin for injection by CentrexionCorporation), CR845 (by Cara Therapeutics), ASP7962 (by AstellasPharma), DA-5202 (by Dong-A ST Co., Ltd.), GZ389988 (by Sanofi-Genzyme),and MEDI 7352 (by AstraZeneca), LNA043 (by Novartis).

4. Kits

Also provided herein are kits. Typically, a kit includes one or moreformulations as described herein, e.g., a single-dose, ready-to-useformulation prepared by the process provided herein comprising acompound of Formula (I), including amorphous and polymorph formsthereof. In certain embodiments, a kit can include one or more deliverysystems, e.g., for delivering or administering the formulation asprovided herein, and directions for use of the kit (e.g., instructionsfor treating a patient). In some embodiments, the kit can include aformulation as described herein and a label that indicates that thecontents are to be administered to a patient with bone or cartilagediseases or osteoarthritis. The actual dose of the compound of Formula(I) provided herein depends on the specific compound, and on thecondition to be treated; the selection of the appropriate dose is wellwithin the knowledge of the skilled artisan.

5. Methods for Treating Osteoarthritis

Provided are methods for the treatment of osteoarthritis in a subject.The methods comprise administering to the subject a therapeuticallyeffective amount of a single-dose, ready-to-use formulation providedherein comprising a compound of Formula (I), including salt andamorphous or polymorph forms thereof. In some embodiments, theformulation is prepared by the process provided herein. In someembodiments, the methods provided herein include intra-articularadministration of a single-dose, ready-to-use pharmaceutical formulationcomprising a therapeutically effective amount of a compound of Formula(I), including salt and amorphous and polymorph forms thereof. In someembodiments, the methods provided herein include intra-articularadministration of a single-dose, ready-to-use pharmaceutical formulationprepared by a process provided herein. In some embodiments, thepolymorph form is Form 1. In some embodiments, the polymorph form is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water.

In some embodiments, provided herein are methods for treatingosteoarthritis in a subject comprising intra-articular administration tothe subject a single-dose, ready-to-use pharmaceutical formulationcomprising a therapeutically effective amount of a compound of Formula(I). In some embodiments, the compound of Formula (I) in the formulationcomprises Form 1. In some embodiments, the compound of Formula (I) inthe formulation comprises a non-stoichiometric or stoichiometric hydrateof Form 1 having between 1% and about 20% by weight water. In someembodiments, the compound of Formula (I) in the formulation issubstantially present as a non-stoichiometric or stoichiometric hydrateof Form 1 having between 1% and 20% by weight water.

In some embodiments of the method provided herein, the single-dose,ready-to-use formulations prepared by the process provided hereincomprising a compound of Formula (I), including amorphous and polymorphforms thereof, are administered parenterally, including intramuscularly,intra-articularly, periarticularly, intradiscal, intraspinally,intrasynovially, and epidurally. In some embodiments, the formulation isadministered to a patient with disc degeneration. In some embodiments,the formulation is administered to a patient with osteoarthritis. Insome embodiments, the formulation can be a bursa injection, a caudalinjection (e.g., a caudal epidural steroid injection (ESI)), a facetinjection, a facet synovial injection, a hip joint injection, anintradiscal injection, an occipital nerve injection, asciatic/piriformis injection, a sacroiliac (SI) joint injection, orcombinations thereof. In some embodiments, the formulation can beinjected locally, for example, in a patient with osteoarthritis, at thesite of osteoarthritis (e.g., knee, hip, shoulder, etc.). Injections canoccur at one or more locations surrounding the joint. In someembodiments, the formulation is administered intra-articularly. In someembodiments, the injection is guided using an imaging method such asultrasound. In some embodiments, administration (e.g., injection) of theformulation is preceded or combined with a local anesthetic.

In some embodiments of the methods provided herein, the formulationcomprising a compound of Formula (I), including salt and amorphous andpolymorph forms thereof, is administered once. In some embodiments, theformulation comprising a compound of Formula (I), including salt andamorphous and polymorph forms thereof, is administered more than once.For example, the formulation is administered by injections spaced atleast 7 days apart. In some embodiments, the formulation is administeredonce every two weeks. In some embodiments, the formulation isadministered once every three weeks. In some embodiments, theformulation is administered once every four weeks. In some embodiments,the formulation is administered once every six weeks. In someembodiments, the formulation is administered once every eight weeks. Insome embodiments, the formulation is administered once every twelveweeks (three months).

6. Polymorphs

Provided herein are formulations comprising a compound of Formula (I):

including pharmaceutically acceptable salts and amorphous and polymorphforms thereof.

The compound of Formula (I) provided herein can be prepared usingmethods known and understood by those of ordinary skill in the art. Forexample, synthetic methods such as those described in PCT/US2013/031055can be used, and this application is herein incorporated by reference inits entirety.

The formulations provided herein can contain a polymorph form of thecompound of Formula (I). The forms include, e.g., solvates, hydrates,non-stoichiometric or stoichiometric hydrates, and non-solvated forms ofthe compound of Formula (I), including, for example, polymorph Forms 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13.

One such polymorph is a polymorph known as Form 1. Form 1 is ananhydrous polymorph of the compound of Formula (I). In one embodiment,Form 1 has an X-ray powder diffraction (XRPD or XRD) pattern, obtainedwith CuKα1-radiation, with at least peaks at ° 2θ values of 6.8±0.2,12.4±0.2, and 18.5±0.2. In some embodiments, Form 1 has an XRPD patternwith at least peaks at ° 2θ values of 6.8±0.2, 12.4±0.2, 16.5±0.2,18.5±0.2, and 19.2±0.2. In some embodiments, Form 1 has an XRPD patternwith at least peaks at ° 2θ values of 6.8±0.2, 9.3±0.2, 12.4±0.2,13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2. For example, insome embodiments, Form 1 has an XRPD pattern with at least peaks at ° 2θvalues of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 14.5±0.2, 16.5±0.2,18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

In some embodiments, the formulations provided herein comprise acomposition comprising polymorph Form 1. In some embodiments, thecomposition can be substantially pure. For example, the composition hasa purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than about 15%by weight of other forms of the compound of Formula (I). For example,the composition can contain less than 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weight of other anhydrous forms ofthe compound of Formula (I). In some embodiments, the compositioncontains less than about 15% by weight of the polymorph Form 9. Forexample, the composition can contain less than 14%, 13%, 12%, 11%, 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weight of the polymorph ofForm 9. In some embodiments, the composition contains less than about15% by weight of one or more other forms of the compound of Formula (I),such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1% or less by weight of one or more other forms of the compound ofFormula (I). For example, the composition can contain less than about15% of Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9,Form 10, and Form 11, a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water, or a combinationof two or more thereof.

In some embodiments, provided herein is a formulation comprisingpolymorph Form 1 that exhibits an endotherm between about 50-100° C. asmeasured by differential scanning calorimetry (DSC) related to sorbedwater. In some embodiments, polymorph Form 1 exhibits arecrystallization event that is observed between about 270-290° C.,e.g., around 280° C. In some embodiments, the endotherm and exotherm areobserved when using a scan rate of 10° C. per minute.

In some embodiments, provided herein is a formulation comprisingpolymorph Form 1 that recrystallizes into Form 9 with a melting point ofaround 363° C. In some embodiments, polymorph Form 1 undergoes a totalmass loss of about 0.33% before around 100° C., e.g., from about 39° C.to about 100° C., as measured by thermal gravimetric analysis (TGA).

In some embodiments, polymorph Form 1 is prepared by a method comprisingdrying a composition comprising the compound of Formula (I), includingamorphous and polymorph forms thereof, to generate polymorph Form 1. Insome embodiments, the composition comprises a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, polymorph Form 1 is prepared by amethod comprising reslurrying a composition comprising the compound ofFormula (I), including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate polymorph Form 1 as aresidual solid. In some embodiments, the reslurrying takes place at roomtemperature (RT). In some embodiments, the reslurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 1 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof in a solvent or mixtureof solvents to generate polymorph Form 1 as a residual solid. In someembodiments, the compound of Formula (I) is a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the solvent is methanol. In someembodiments, the solvent is toluene. In some embodiments, the solvent isheptane. In some embodiments, the solvent is dichloromethane (DCM). Insome embodiments, the solvent is water. In some embodiments, the solventis in a mixture with water, for example the solvent can be a mixture ofwater and acetonitrile, methanol, ethyl acetate (EA), methyl tert-butylether (MtBE), isopropyl alcohol (IPAc), methyl acetate (MA), methylisobutyl ketone (MIBK), DCM, n-butyl acetate, heptane, toluene, orn-butanol. In some embodiments, the water is present in an amount ofabout 5% by weight. In some embodiments, the reslurrying takes place atroom temperature. In some embodiments, the reslurrying takes place ataround 50° C. In some embodiments, polymorph Form 1 is prepared by amethod further comprising drying the residual solid, for example, undervacuum. In some embodiments, the drying is at a temperature of betweenabout 60° C. and 90° C., such as, e.g., around 75° C.

Provided herein are formulations comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, for example, above 30% relativehumidity (RH), Form 1 readily sorbs water and shows a distinctive shiftin Form 1 peaks from 6.8±0.2 to 6.2±0.2 and 12.6±0.2 to 11±0.2. In someembodiments, a non-stoichiometric or stoichiometric hydrate of Form 1comprises up to about 20% by weight water. For example, up to about 20%,about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%,about 6%, about 5%, about 4%, about 3%, about 2%, or greater than 1%water by weight. In some embodiments, a non-stoichiometric orstoichiometric hydrate of Form 1 has between 1 to about 20% water byweight, e.g., between 1% and about 10%, about 5% and about 15%, about10% and about 20%, 1% and about 5%, about 5% and about 10%, about 10%and about 15%, about 15% and about 20%, or about 17% and about 20% waterby weight.

In some embodiments, provided herein is a formulation comprising acomposition comprising a non-stoichiometric or stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water. In someembodiments, the composition is substantially pure. For example, thecomposition can have a purity of at least about 90%. In someembodiments, the composition has a purity of at least about 95%. In someembodiments, the composition has a purity of at least about 98%. Forexample, the composition can have a purity of at least 98.5%, 98.6%,98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%,99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of the compound of Formula (I). Forexample, in some embodiments, the composition is substantially free ofanhydrous forms of the compound of Formula (I). In some embodiments, thecomposition contains less than 15% by weight of other forms of thecompound of Formula (I), such as less than 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weight of other forms of thecompound of Formula (I) (e.g., anhydrous forms of the compound ofFormula (I)). In some embodiments, the composition contains less than20% by weight of polymorph Form 9 having X-ray powder diffractionpattern comprising peaks at ° 2θ values of 4.9±0.2, 18.6±0.2, and21.1±0.2. For example, the composition contains less than 15% by weightof Form 9, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1% or less by weight of other forms of the compound ofForm 9. In some embodiments, the composition contains less than 15% ofone or more other forms of the compound of Formula (I), such as lessthan 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lessof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, ora combination of two or more thereof.

Another example of a non-stoichiometric hydrate of polymorph Form 1 isreferred to as Form 12.

In one embodiment, provided herein is a formulation comprising polymorphForm 12. In some embodiments, Form 12 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ positions 6.4±0.2,11.0±0.2, and 18.4±0.2. In some embodiments, Form 12 has an XRPD patternwith at least peaks at ° 2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2,18.4±0.2, and 19.7±0.2. In some embodiments, Form 12 has an XRPD patternwith at least peaks at ° 2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2,15.6±0.2, 18.4±0.2, 19.7±0.2, 24.4±0.2, and 25.2±0.2. For example, insome embodiments, Form 12 has an XRPD pattern with at least peaks at °2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2, 15.6±0.2, 16.1±0.2, 18.4±0.2,19.7±0.2, 20.8±0.2, 24.4±0.2, and 25.2±0.2.

In some embodiments, provided herein is polymorph Form 12 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 12 exhibits an exotherm at around 283° C. Insome embodiments, the endotherms and exotherms are observed when using ascan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 12 that has amelting point of around 364° C. In some embodiments, polymorph Form 12undergoes a weight loss of about 1.4% before around 100° C., e.g., fromabout 30° C. to about 100° C., as measured by TGA.

One example of a non-stoichiometric hydrate of polymorph Form 1 isreferred to as Form 13.

In one embodiment, provided herein is a formulation comprising polymorphForm 13. In some embodiments, polymorph Form 13 has an XRPD pattern,obtained with CuKα1-radiation, with at least peaks at ° 2θ values of6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, Form 13 has anXRPD pattern with at least peaks at ° 2θ values of 6.8±0.2, 12.4±0.2,16.5±0.2, 18.5±0.2, and 19.2±0.2. In some embodiments, Form 13 has anXRPD pattern with at least peaks at ° 2θ values of 6.8±0.2, 9.3±0.2,12.4±0.2, 13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2. Forexample, in some embodiments, Form 13 has an XRPD pattern with at leastpeaks at ° 2θ values of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 14.5±0.2,16.5±0.2, 18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

In some embodiments, polymorph Form 13 exhibits an endotherm betweenabout 50-100° C. as measured by DSC. In some embodiments, polymorph Form13 exhibits an exotherm at between about 265-285° C., e.g., around 278°C. For example, in some embodiments, the endotherms and exotherms areobserved when using a scan rate of 10° C. per minute.

In some embodiments, polymorph Form 13 has a melting point of around363° C. In some embodiments, polymorph Form 13 undergoes a weight lossof about 1.9% before around 100° C. as measured by TGA.

Provided herein are methods of preparing a non-stoichiometric orstoichiometric hydrate of polymorph Form 1. In some embodiments, themethod comprises reslurrying a composition comprising the compound ofFormula (I), including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate a non-stoichiometric orstoichiometric hydrate of polymorph Form 1 as a residual solid. In someembodiments, the composition comprising the compound of Formula (I) is amixture of a non-stoichiometric or stoichiometric hydrate of polymorphForm 1 and Form 1. In some embodiments, the reslurrying takes place atRT. In some embodiments, the reslurrying takes place at around 50° C. Insome embodiments, the method further comprises drying the residualsolid, for example, under vacuum. In some embodiments, the drying is ata temperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a mixture of a non-stoichiometric or stoichiometric hydrateof polymorph Form 1 and Form 1 in a solvent or mixture of solvents togenerate a non-stoichiometric or stoichiometric hydrate of polymorphForm 1 as a residual solid. In some embodiments, the solvent is in amixture with water, for example the solvent can be a mixture of waterand acetonitrile, methanol, MtBE, MA, MIBK, DCM, IPAc, n-butyl acetate,heptane, toluene, or n-butanol. In some embodiments, the water ispresent in an amount of about 5% by weight. In some embodiments, thereslurrying takes place at RT. In some embodiments, the reslurryingtakes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 2.Form 2 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 2 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 7.0±0.2,21.5±0.2, and 22.0±0.2. In some embodiments, Form 2 has an XRPD patternwith at least peaks at ° 2θ values of 7.0±0.2, 18.9±0.2, 21.5±0.2,22.0±0.2, and 24.2±0.2. In some embodiments, Form 2 has an XRPD patternwith at least peaks at ° 2θ values of 7.0±0.2, 14.1±0.2, 18.9±0.2,19.2±0.2, 21.5±0.2, 22.0±0.2, 24.2±0.2, and 26.4±0.2. For example, insome embodiments, Form 2 has an XRPD pattern with at least peaks at ° 2θvalues of 7.0±0.2, 10.4±0.2, 14.1±0.2, 17.6±0.2, 18.9±0.2, 19.2±0.2,21.5±0.2, 22.0±0.2, 24.2±0.2, and 26.4±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 2. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 3, Form4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 2 exhibits an endotherm betweenabout 50-100° C. as measured by DSC. In some embodiments, polymorph Form2 exhibits an endotherm between about 220-230° C. In some embodiments,polymorph Form 2 exhibits an exotherm between about 233-238° C. In someembodiments, polymorph Form 2 exhibits an exotherm between about290-295° C. In some embodiments, the endotherms and exotherms areobserved when using a scan rate of 10° C. per minute.

In some embodiments, polymorph Form 2 has a melting point of around 363°C. In some embodiments, polymorph Form 2 undergoes a weight loss ofabout 2.7% before around 116° C., e.g., from about 36° C. to about 116°C., as measured by TGA.

In some embodiments, polymorph Form 2 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 2 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) comprises anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 2 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 2 as a residual solid. In some embodiments, the solvent isacetonitrile. In some embodiments, the solvent is ethanol. In someembodiments, the solvent is in a mixture with water, for example thesolvent can be a mixture of water and ethanol or water and n-propanol.In some embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 3.Form 3 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 3 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 7.2±0.2,22.2±0.2, and 24.4±0.2. In some embodiments, Form 3 has an XRPD patternwith at least peaks at ° 2θ values of 6.3±0.2, 7.2±0.2, 21.6±0.2,22.2±0.2, and 24.4±0.2. In some embodiments, Form 3 has an XRPD patternwith at least peaks at ° 2θ values of 6.3±0.2, 7.2±0.2, 11.0±0.2,18.4±0.2, 19.0±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2. For example, insome embodiments, Form 3 has an XRPD pattern with at least peaks at ° 2θvalues of 6.3±0.2, 7.2±0.2, 11.0±0.2, 14.2±0.2, 17.8±0.2, 18.4±0.2,19.0±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 3. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 3 exhibits an exotherm between about190-220° C., as measured by DSC. In some embodiments, polymorph Form 3exhibits an exotherm at between about 225-235° C., e.g., around 230° C.,as measured by DSC. In some embodiments, polymorph Form 3 exhibits anexotherm at between about 292-300° C., e.g., around 297° C., as measuredby DSC. For example, in some embodiments, the endotherms and exothermsare observed when using a scan rate of 10° C. per minute.

In some embodiments, polymorph Form 3 has a melting point of around 365°C. In some embodiments, polymorph Form 3 undergoes a weight loss ofabout 1.6% before around 81° C. and a weight loss of about 1.7% betweenabout 81-169° C. as measured by TGA.

In some embodiments, polymorph Form 3 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 3 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) comprises anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 3 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 3 as a residual solid. In some embodiments, the solvent is IPAc. Insome embodiments, the solvent is n-butyl acetate. In some embodiments,the reslurrying takes place at RT. In some embodiments, the reslurryingtakes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 4.Form 4 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 4 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 7.0±0.2,21.8±0.2, and 25.1±0.2. In some embodiments, Form 4 has an XRPD patternwith at least peaks at ° 2θ values of 7.0±0.2, 19.5±0.2, 21.8±0.2,23.2±0.2, and 25.1±0.2. In some embodiments, Form 4 has an XRPD patternwith at least peaks at ° 2θ values of 7.0±0.2, 17.6±0.2, 18.3±0.2,19.5±0.2, 21.8±0.2, 23.2±0.2, 25.1±0.2, and 25.8±0.2. For example, insome embodiments, Form 4 has an XRPD pattern with at least peaks at ° 2θvalues of 7.0±0.2, 9.6±0.2, 17.6±0.2, 18.3±0.2, 19.5±0.2, 21.8±0.2,23.2±0.2, 25.1±0.2, 25.8±0.2, and 29.3±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 4. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 4 exhibits an endotherm betweenabout 50-100° C. as measured by DSC. In some embodiments, polymorph Form4 exhibits an endotherm at between about 180-215° C. In someembodiments, polymorph Form 4 exhibits an endotherm between about220-230° C. In some embodiments, polymorph Form 4 exhibits an exothermat between about 230-240° C., e.g., around 235° C. In some embodiments,polymorph Form 4 exhibits an exotherm at between about 300-310° C. Forexample, in some embodiments, the endotherms and exotherms are observedwhen using a scan rate of 10° C. per minute.

In some embodiments, polymorph Form 4 has a melting point of betweenabout 366-369° C., e.g., around 367° C. In some embodiments, polymorphForm 4 undergoes a weight loss of about 8.3% before around 200° C.,e.g., from about 42° C. to about 200° C., as measured by TGA.

In some embodiments, polymorph Form 4 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 4 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) comprises anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 4 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 4 as a residual solid. In some embodiments, the solvent is EA. Insome embodiments, the solvent is MA. In some embodiments, the solvent isMtBE. In some embodiments, the solvent is n-propanol. In someembodiments, the solvent is acetone. In some embodiments, the solvent isin a mixture with water, for example the solvent can be a mixture ofwater and MA, EA, or acetone. In some embodiments, the water is presentin an amount of about 5% by weight. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the reslurrying takes place ataround 50° C.

Provided herein is a formulation comprising a polymorph known as Form 5.Form 5 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 5 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 7.3±0.2,22.3±0.2, and 24.5±0.2. In some embodiments, Form 5 has an XRPD patternwith at least peaks at ° 2θ values of 6.3±0.2, 7.3±0.2, 21.7±0.2,22.3±0.2, and 24.5±0.2. In some embodiments, Form 5 has an XRPD patternwith at least peaks at ° 2θ values of 6.3±0.2, 7.3±0.2, 11.0±0.2,19.1±0.2, 19.5±0.2, 21.7±0.2, 22.3±0.2, and 24.5±0.2. For example, insome embodiments, Form 5 has an XRPD pattern with at least peaks at ° 2θvalues of 6.3±0.2, 7.3±0.2, 11.0±0.2, 14.3±0.2, 19.1±0.2, 19.5±0.2,21.7±0.2, 22.3±0.2, 24.5±0.2, and 26.5±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 5. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 5 exhibits an endotherm betweenabout 50-100° C. as measured by DSC. In some embodiments, polymorph Form5 exhibits an endotherm at between about 210-235° C., e.g., around 222°C. In some embodiments, polymorph Form 5 exhibits an exotherm at betweenabout 227-240° C., e.g., around 235° C. In some embodiments, polymorphForm 5 exhibits an exotherm at between about 280-300° C., e.g., around293° C. For example, in some embodiments, the endotherms and exothermsare observed when using a scan rate of 10° C. per minute.

In some embodiments, polymorph Form 5 has a melting point of around 363°C. In some embodiments, polymorph Form 5 undergoes a weight loss ofabout 3.1% before around 100° C. and about 1.7% between about 100-250°C. as measured by TGA.

In some embodiments, polymorph Form 5 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 5 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) comprises anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 5 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 5 as a residual solid. In some embodiments, the solvent is MtBE. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 6.Form 6 is an anhydrous polymorph of the compound of Formula (I).

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 6. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 7, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 6 exhibits an exotherm between about245-260° C. as measured by DSC. For example, in some embodiments, theendotherms and exotherms are observed when using a scan rate of 10° C.per minute. In some embodiments, polymorph Form 6 has a melting point ofaround 364° C.

In some embodiments, polymorph Form 6 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 6 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 6 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 6 as a residual solid. In some embodiments, the solvent is IPAc. Insome embodiments, the solvent is in a mixture with water, for examplethe solvent can be a mixture of water and IPAc. In some embodiments, thewater is present in an amount of about 5% by weight. In someembodiments, the reslurrying takes place at RT. In some embodiments, thereslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 7.Form 7 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 7 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 7.1±0.2,21.6±0.2, and 23.2±0.2. In some embodiments, Form 7 has an XRPD patternwith at least peaks at ° 2θ values of 4.9±0.2, 7.1±0.2, 18.5±0.2,21.6±0.2, and 23.2±0.2. In some embodiments, Form 7 has an XRPD patternwith at least peaks at ° 2θ values of 4.9±0.2, 7.1±0.2, 10.9±0.2,18.5±0.2, 19.4±0.2, 21.6±0.2, 23.2±0.2, and 30.3±0.2. For example, insome embodiments, Form 7 has an XRPD pattern with at least peaks at ° 2θvalues of 4.9±0.2, 7.1±0.2, 8.8±0.2, 10.9±0.2, 18.5±0.2, 19.4±0.2,21.6±0.2, 22.1±0.2, 23.2±0.2, and 30.3±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 7. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 8, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 7 exhibits an exotherm between about227-235° C., e.g., around 232° C., as measured by DSC. In someembodiments, polymorph Form 7 exhibits an exotherm between about299-305° C., e.g., around 303° C. For example, in some embodiments, theendotherms and exotherms are observed when using a scan rate of 10° C.per minute.

In some embodiments, polymorph Form 7 has a melting point of around 365°C. In some embodiments, polymorph Form 7 undergoes a weight loss ofabout 12% before around 200° C., e.g., from about 36° C. to about 200°C., as measured by TGA.

In some embodiments, polymorph Form 7 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 7 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 7 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 7 as a residual solid. In some embodiments, the solvent is methylethyl ketone (MEK). In some embodiments, the solvent is in a mixturewith water, for example the solvent can be a mixture of water and MEK.In some embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 8.Form 8 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 8 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 6.9±0.2,17.7±0.2, and 21.5±0.2. In some embodiments, Form 8 has an XRPD patternwith at least peaks at ° 2θ values of 6.9±0.2, 11.5±0.2, 17.7±0.2,21.5±0.2, and 27.6±0.2. In some embodiments, Form 8 has an XRPD patternwith at least peaks at ° 2θ values of 6.9±0.2, 11.5±0.2, 15.3±0.2,16.9±0.2, 17.7±0.2, 21.5±0.2, 27.6±0.2, and 28.9±0.2. For example, insome embodiments, Form 8 has an XRPD pattern with at least peaks at ° 2θvalues of 6.9±0.2, 11.5±0.2, 12.7±0.2, 14.2±0.2, 15.3±0.2, 16.9±0.2,17.7±0.2, 21.5±0.2, 27.6±0.2, and 28.9±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 8. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 7, Form 9, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 8 exhibits an endotherm betweenabout 41-60° C. as measured by DSC. In some embodiments, polymorph Form8 exhibits an exotherm at between about 221-235° C., e.g., around 231°C. In some embodiments, polymorph Form 8 exhibits an endotherm betweenabout 279-290° C., e.g., around 285° C. For example, in someembodiments, the endotherms and exotherms are observed when using a scanrate of 10° C. per minute.

In some embodiments, polymorph Form 8 has a melting point of around 364°C. In some embodiments, polymorph Form 8 undergoes a weight loss ofabout 4.2% before around 190° C. and about 3.9% between about 190-261°C. as measured by TGA.

In some embodiments, polymorph Form 8 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 8 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 8 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 8 as a residual solid. In some embodiments, the solvent is MIBK. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form 9.Form 9 is an anhydrous polymorph of the compound of Formula (I). In oneembodiment, polymorph Form 9 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 4.9±0.2,18.6±0.2, and 21.1±0.2. In some embodiments, Form 9 has an XRPD patternwith at least peaks at ° 2θ values of 4.9±0.2, 18.6±0.2, 21.1±0.2,24.1±0.2, and 25.2±0.2. In some embodiments, Form 9 has an XRPD patternwith at least peaks at ° 2θ values of 4.9±0.2, 15.3±0.2, 16.5±0.2,18.6±0.2, 21.1±0.2, 22.4±0.2, 24.1±0.2, and 25.2±0.2. For example, insome embodiments, Form 9 has an XRPD pattern with at least peaks at ° 2θvalues of 4.9±0.2, 10.1±0.2, 15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2,22.4±0.2, 24.1±0.2, 25.2±0.2, and 28.6±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 9. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 10, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 9 exhibits a single meltingendotherm at around 364° C. as measured by DSC. For example, in someembodiments, the endotherm is observed when using a scan rate of 10° C.per minute. In some embodiments, other polymorph forms provided herein,such as, e.g., Form 1 and Form 2, can convert to Form 9 when heated tojust before melting (i.e., around 364° C.).

In some embodiments, polymorph Form 9 has a melting point of around 364°C. In some embodiments, polymorph Form 9 undergoes a weight loss ofabout 0.28% before around 100° C., e.g., from about 30.5° C. to about100° C., as measured by TGA.

In some embodiments, polymorph Form 9 is prepared by a method comprisingreslurrying a composition comprising the compound of Formula (I),including amorphous and polymorph forms thereof, in a solvent or mixtureof solvents to generate Form 9 as a residual solid. In some embodiments,the composition comprising the compound of Formula (I) is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 9 is prepared by a method comprisingreslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 9 as a residual solid. In some embodiments, the solvent isn-butanol. In some embodiments, the solvent is IPAc. In someembodiments, the solvent is n-butyl acetate. In some embodiments, thesolvent is in a mixture with water, for example the solvent can be amixture of water and ethanol or water and n-propanol. In someembodiments, the water is present in an amount of about 5% by weight. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form10. Polymorph Form 10 is a polymorph of the compound of Formula (I)comprising DMSO. For example, DMSO is on the surface of the polymorph.In one embodiment, polymorph Form 10 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 20.7±0.2,21.7±0.2, and 24.2±0.2. In some embodiments, Form 10 has an XRPD patternwith at least peaks at ° 2θ values of 18.2±0.2, 19.0±0.2, 20.7±0.2,21.7±0.2, and 24.2±0.2. In some embodiments, Form 10 has an XRPD patternwith at least peaks at ° 2θ values of 17.8±0.2, 18.2±0.2, 19.0±0.2,20.7±0.2, 21.7±0.2, 23.4±0.2, 24.2±0.2, and 27.9±0.2. For example, insome embodiments, Form 10 has an XRPD pattern with at least peaks at °2θ values of 6.7±0.2, 17.8±0.2, 18.2±0.2, 19.0±0.2, 19.9±0.2, 20.7±0.2,21.7±0.2, 23.4±0.2, 24.2±0.2, and 27.9±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 10. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 11, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 10 exhibits an endotherm betweenabout 212-237° C. as measured by DSC. In some embodiments, polymorphForm 10 exhibits an endotherm at between about 234-245° C., e.g., around237° C. In some embodiments, polymorph Form 10 exhibits an exothermbetween about 300-325° C., e.g., around 308° C. For example, in someembodiments, the endotherms and exotherms are observed when using a scanrate of 10° C. per minute.

In some embodiments, polymorph Form 10 has a melting point of betweenabout 364-372° C., such as, e.g., around 369° C. In some embodiments,polymorph Form 10 undergoes a weight loss of about 0.6% before around100° C., a weight loss of about 3.8% between about 100-170° C., and aweight loss of about 7.1% between about 170-260° C. as measured by TGA.

In some embodiments, polymorph Form 10 is prepared by a methodcomprising reslurrying a composition comprising the compound of Formula(I), including amorphous and polymorph forms thereof, in a solvent ormixture of solvents to generate Form 10 as a residual solid. In someembodiments, the composition comprising the compound of Formula (I) is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 10 is prepared by a methodcomprising reslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 10 as a residual solid. In some embodiments, the solvent is DMSO.In some embodiments, the solvent is in a mixture with water, for examplethe solvent can be a mixture of water and DMSO. In some embodiments, thewater is present in an amount of about 5% by weight. In someembodiments, the reslurrying takes place at RT. In some embodiments, thereslurrying takes place at around 50° C.

Provided herein is a formulation comprising a polymorph known as Form11. Form 11 is an anhydrous polymorph of the compound of Formula (I). Inone embodiment, polymorph Form 11 has an XRPD pattern, obtained withCuKα1-radiation, with at least peaks at ° 2θ values of 6.4±0.2,18.5±0.2, and 22.4±0.2. In some embodiments, Form 11 has an XRPD patternwith at least peaks at ° 2θ values of 6.4±0.2, 17.8±0.2, 18.5±0.2,19.9±0.2, and 22.4±0.2. In some embodiments, Form 11 has an XRPD patternwith at least peaks at ° 2θ values of 6.4±0.2, 8.4±0.2, 17.8±0.2,18.5±0.2, 19.9±0.2, 22.4±0.2, 24.5±0.2, and 26.8±0.2. For example, insome embodiments, Form 11 has an XRPD pattern with at least peaks at °2θ values of 6.4±0.2, 8.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, 20.3±0.2,22.4±0.2, 22.9±0.2, 24.5±0.2, and 26.8±0.2.

In some embodiments, provided herein is a formulation comprising acomposition comprising polymorph Form 11. In some embodiments, thecomposition is substantially pure. For example, the composition can havea purity of at least about 90%. In some embodiments, the composition hasa purity of at least about 95%. In some embodiments, the composition hasa purity of at least about 98%. For example, the composition can have apurity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments,the composition is substantially free of other forms of the compound ofFormula (I). For example, in some embodiments, the composition issubstantially free of other anhydrous forms of the compound of Formula(I). In some embodiments, the composition contains less than 15% byweight of other forms of the compound of Formula (I), such as less than14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less byweight of other forms of the compound of Formula (I). In someembodiments, the composition contains less than 15% by weight of one ormore other forms of the compound of Formula (I), such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof one or more other forms of the compound of Formula (I). For example,the composition can contain less than about 15% of Form 1, Form 2, Form3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, anon-stoichiometric or stoichiometric hydrate of Form 1, or a combinationof two or more thereof.

In some embodiments, polymorph Form 11 exhibits an endotherm betweenabout 215-230° C. as measured by DSC. In some embodiments, polymorphForm 11 exhibits an exotherm at between about 230-240° C., e.g., around235° C. In some embodiments, polymorph Form 11 exhibits an exothermbetween about 300-315° C., e.g., around 310° C. For example, in someembodiments, the endotherms and exotherms are observed when using a scanrate of 10° C. per minute.

In some embodiments, polymorph Form 11 has a melting point of around368° C. In some embodiments, polymorph Form 11 undergoes a weight lossof about 0.8% before around 100° C. and a weight loss of about 7.0%between about 100-249° C., as measured by TGA.

In some embodiments, polymorph Form 11 is prepared by a methodcomprising reslurrying a composition comprising the compound of Formula(I), including amorphous and polymorph forms thereof, in a solvent ormixture of solvents to generate Form 11 as a residual solid. In someembodiments, the composition comprising the compound of Formula (I) is anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. In some embodiments, the reslurryingtakes place at RT. In some embodiments, the slurrying takes place ataround 50° C. In some embodiments, the method further comprises dryingthe residual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

In some embodiments, polymorph Form 11 is prepared by a methodcomprising reslurrying a composition comprising a non-stoichiometric orstoichiometric hydrate of Form 1 having between 1% and about 20% byweight water in a solvent or mixture of solvents to generate polymorphForm 11 as a residual solid. In some embodiments, the solvent isdimethylformamide (DMF). In some embodiments, the solvent is in amixture with water, for example the solvent can be a mixture of waterand DMF. In some embodiments, the water is present in an amount of about5% by weight. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the reslurrying takes place at around 50° C.

EXAMPLES Example 1: Preparation of Single-Dose, Ready-to-UseFormulations

Single-dose, ready-to-use formulations containing either 0.015 mg/mL,0.025 mg/mL or 0.115 mg/mL of polymorph Form 1 of the compound ofFormula (I) were prepared. The compound of Formula (I) was preparedaccording to the process provided in US 2013/0267495, incorporatedherein by reference in its entirety. The polymorph of Form 1 wasprepared as described herein.

For a 0.015 mg/mL Formulation:

Water, sodium carboxymethylcellulose (CMC) (5.55 g/kg), polysorbate 80(0.50 g/kg), sodium phosphate monobasic monohydrate (0.268 g/kg), sodiumphosphate dibasic heptahydrate (2.44 g/kg), and sodium chloride (9.11g/kg) were added to a 300 L first tank. The aqueous solution in thefirst tank was then filtered through a 0.2 μm polyethersulfone (PES)filter into a second tank, where it was bulk sterilized. 0.15 g/kg ofpolymorph Form 1 of the compound of Formula (I), water for injection,and 0.5 g/kg polysorbate 80 were added to a 30 L third tank to form aslurry containing 15 μg/mL of the compound of Formula (I). The slurrywas sterilized by overhead steam pressure, then added to the second tankcontaining the aqueous solution. The slurry was homogenized at 30 Hz andmanufactured using principles of overkill cycle (F₀≥30). The mixture wasaseptically mixed with sterile diluent to form a suspension with aconcentration of 0.015 mg/mL of the compound of Formula (I). The bulksolution temperature was maintained at 250° F. as monitored by bottom TCand overhead pressure was maintained greater than the steam pressureintroduced in the tank jacket (˜>5 psi). To maintain overhead pressureduring bleeding of the top valve next to the mixer to monitor TC abovethe tank, steam was introduced via the air filter into the tank tomaintain pressure and high temperature. The steam pressure was monitoredand bulk sterilization performed. The suspension was then asepticallyfilled using a Weiler 624 BFS machine into 3 mL polypropylene vials,with a target volume of 2.5 mL and a final concentration of 0.015 mg/mLof the compound of Formula (I). Each vial contained 0.03 mg of Form 1 ofthe compound of Formula (I) in 2 mL phosphate buffered saline. The vialswere labeled and packaged.

For a 0.035 mg/mL Formulation:

Water, sodium carboxymethylcellulose (CMC) (5.55 g/kg), polysorbate 80(0.50 g/kg), sodium phosphate monobasic monohydrate (0.268 g/kg), sodiumphosphate dibasic heptahydrate (2.44 g/kg), and sodium chloride (9.11g/kg) were added to a 300 L first tank. The aqueous solution in thefirst tank was then filtered through a 0.2 μm polyethersulfone (PES)filter into a second tank, where it was bulk sterilized. 0.35 g/kg ofpolymorph Form 1 of the compound of Formula (I), water for injection,and 0.5 g/kg polysorbate 80 were added to a 30 L third tank to form aslurry containing 35 μg/mL of the compound of Formula (I). The slurrywas sterilized by overhead steam pressure, then added to the second tankcontaining the aqueous solution. The slurry was homogenized at 30 Hz andmanufactured using principles of overkill cycle (F₀≥30). The mixture wasaseptically mixed with sterile diluent to form a suspension with aconcentration of 0.035 mg/mL of the compound of Formula (I). The bulksolution temperature was maintained at 250° F. as monitored by bottom TCand overhead pressure was maintained greater than the steam pressureintroduced in the tank jacket (˜>5 psi). To maintain overhead pressureduring bleeding of the top valve next to the mixer to monitor TC abovethe tank, steam was introduced via the air filter into the tank tomaintain pressure and high temperature. The steam pressure was monitoredand bulk sterilization performed. The suspension was then asepticallyfilled using a Weiler 624 BFS machine into 3 mL polypropylene vials,with a target volume of 2.5 mL and a final concentration of 0.035 mg/mLof the compound of Formula (I). Each vial contained 0.07 mg of Form 1 ofthe compound of Formula (I) in 2 mL phosphate buffered saline. The vialswere labeled and packaged.

For a 0.075 mg/mL Formulation:

Water, sodium carboxymethylcellulose (CMC) (5.55 g/kg), polysorbate 80(0.50 g/kg), sodium phosphate monobasic monohydrate (0.268 g/kg), sodiumphosphate dibasic heptahydrate (2.44 g/kg), and sodium chloride (9.11g/kg) were added to a 300 L first tank. The aqueous solution in thefirst tank was then filtered through a 0.2 μm polyethersulfone (PES)filter into a second tank, where it was bulk sterilized. 0.75 g/kg ofpolymorph Form 1 of the compound of Formula (I), water for injection,and 0.5 g/kg polysorbate 80 were added to a 30 L third tank to form aslurry containing 75 μg/mL of the compound of Formula (I). The slurrywas sterilized by overhead steam pressure, then added to the second tankcontaining the aqueous solution. The slurry was homogenized at 30 Hz andmanufactured using principles of overkill cycle (F₀≥30). The mixture wasaseptically mixed with sterile diluent to form a suspension with aconcentration of 0.075 mg/mL of the compound of Formula (I). The bulksolution temperature was maintained at 250° F. as monitored by bottom TCand overhead pressure was maintained greater than the steam pressureintroduced in the tank jacket (˜>5 psi). To maintain overhead pressureduring bleeding of the top valve next to the mixer to monitor TC abovethe tank, steam was introduced via the air filter into the tank tomaintain pressure and high temperature. The steam pressure was monitoredand bulk sterilization performed. The suspension was then asepticallyfilled using a Weiler 624 BFS machine into 3 mL polypropylene vials,with a target volume of 2.5 mL and a final concentration of 0.075 mg/mLof the compound of Formula (I). Each vial contained 0.15 mg of Form 1 ofthe compound of Formula (I) in 2 mL phosphate buffered saline. The vialswere labeled and packaged.

For a 0.115 mg/mL Formulation:

Water, sodium carboxymethylcellulose (CMC) (5.55 g/kg), polysorbate 80(0.50 g/kg), sodium phosphate monobasic monohydrate (0.268 g/kg), sodiumphosphate dibasic heptahydrate (2.44 g/kg), and sodium chloride (9.11g/kg) were added to a 300 L first tank. The aqueous solution in thefirst tank was then filtered through a 0.2 μm polyethersulfone (PES)filter into a second tank, where it was bulk sterilized. 0.15 g/kg ofpolymorph Form 1 of the compound of Formula (I), water for injection,and 0.5 g/kg polysorbate 80 were added to a 30 L third tank to form aslurry containing 115 μg/mL of the compound of Formula (I). The slurrywas sterilized by overhead steam pressure, then added to the second tankcontaining the aqueous solution. The slurry was homogenized at 30 Hz andmanufactured using principles of overkill cycle (F₀≥30). The mixture wasaseptically mixed with sterile diluent to form a suspension with aconcentration of 0.115 mg/mL of the compound of Formula (I). The bulksolution temperature was maintained at 250° F. as monitored by bottom TCand overhead pressure was maintained greater than the steam pressureintroduced in the tank jacket (˜>5 psi). To maintain overhead pressureduring bleeding of the top valve next to the mixer to monitor TC abovethe tank, steam was introduced via the air filter into the tank tomaintain pressure and high temperature. The steam pressure was monitoredand bulk sterilization performed. The suspension was then asepticallyfilled using a Weiler 624 BFS machine into 3 mL polypropylene vials,with a target volume of 2.5 mL and a final concentration of 0.035 mg/mLof the compound of Formula (I). Each vial contained 0.23 mg of Form 1 ofthe compound of Formula (I) in 2 mL phosphate buffered saline. The vialswere labeled and packaged.

Example 2: Polymorph Screen

A polymorph form of the compound of Formula (I) was used in theready-to-use formulations described in Example 1, above. A polymorphscreen was performed on the compound of Formula (I) to determinesolubility, polymorphism, and thermodynamic stability.

A. Analysis of the Starting Solid

X-ray powder diffraction (XRD), differential scanning calorimetry (DSC),and thermal gravimetric analysis (TGA) scans of the starting solidcompound of Formula (I) indicated that the starting solid was acrystalline material and was a mixture of Form 1 and anon-stoichiometric or stoichiometric hydrate of Form 1 having between 1%and about 20% by weight water. According to the DSC scan (FIG. 12B), thesolid showed a wide endotherm between 50° C.-100° C.; it also showed asharp exotherm at 284° C.; and the solid eventually melted at 364° C.According to the TGA scan (FIG. 12C), a 1.4% weight loss was observedbefore 100° C.

The solubility of the starting solid was measured by the gravimetricmethod and indicated that the compound had low solubility at RT and at50° C. in all solvents tested except DMF and DMSO. Results from thesolubility data test at RT and at 50° C. are shown in Table 3.

TABLE 3 Solubility data of the starting solid (a non-stoichiometric orstoichiometric hydrate of Form 1) Solubility at RT Solubility at 50° C.Solvents (mg/mL) (mg/mL) Acetone 1 1 Acetonitrile ~0 0 MeOH 1 1 Toluene1 1 EtOH 2 2 IPAc ~0 ~0 EA 1 1 MtBE ~0 ~0 IPA 2 5 MEK 1 1 MA ~0 ~0n-Propanol 1 2 MIBK 1 1 n-Butyl acetate ~0 ~0 water 1 1 Heptane ~0 ~0n-Butanol 1 2 DMSO n/a n/a DMF 12 16 DCM 2 2 Acetic acid ~0 3

Reslurry experiments in various solvents were performed. Approximately30-80 mg of the starting solid (a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water) wasslurried in 39 different solvents (pure and binary solvents; the ratioof organic solvent/water (V/V) was 95%/5%) at RT and 50° C. for 5 days.Three solvates, one hydrate, and eleven non-solvated forms wereidentified. A “*” after a particular Form, e.g., Form 2*, indicates thatthe forms had similar XRD scans with minor differences and wereconsidered to belong to the same class. Generally, the identified formsshowed multiple endotherms/exotherms on differential scanningcalorimetry (DSC) scans; Form 9 showed a single endotherm. XRD of bothwet and dry samples were scanned (FIG. 12A (dry sample)). The data isshown in Tables 4 and 5 below.

TABLE 4 Results of slurry experiments at RT Crystalline Form CrystallineForm Solvent (wet/dry) Solvent (wet/dry) Acetone Solvate 1 Form 2Acetone/water Solvate 2 Form 4** Acetonitrile Form 2 Form 1Acetonitrile/ Form 12 Form 1 MeOH Form 13 Form 1 water Toluene Form 1Form 2* MeOH/water Form 12 Form 1 EtOH Form 2* Form 3 Toluene/water Form13 Form 1 IPAc Form 3 Form 4 EtOH/water Solvate 3 Form 2 EA Form 4* Form5 IPAc/water Form 12 Form 1 MtBE Form 5* Form 6 EA/water Form 12 Form 1IPA Form 6 Form 7 MtBE/water Form 12 Form 1 MEK Form 7 Form 4 IPA/waterForm 6 Form 6 MA Form 4 Form 4* MEK/water Form 7 Form 7 n-Propanol Form4* Form 8 MA/water Form 13 Form 1 MIBK Form 8 Form 3 n-Propanol/ Form2** Form 2** n-Butyl Form 3* Form 1 water acetate MIBK/water Form 12Form 1 Water Form 13 Form 1 n-Butyl Form 13 Form 12 Heptane Form 1 Form9 acetate/water n-Butanol Form 9 Form 10 Heptane/water Form 13 Form 12DMSO amorphous Form 11 n-Butanol/water Form 13 Form 13 DMF Form 11 Form1 DMSO/water amorphous Form 10 DCM Form 1 Form 2 DMF/water Form 11 Form11 DCM/water Form 13 Form 1

TABLE 5 Results of slurry experiments at 50° C. Crystalline FormCrystalline Form Solvent (wet/dry) Solvent (wet/dry) Acetone Solvate 2Form 4** Acetone/water Form 4** Form 4** Acetonitrile Form 2* Form 2Acetonitrile/water Form 13 Form 13 MeOH Form 1 Form 1 MeOH/water Form 13Form 13 Toluene Form 1 Form 1 Toluene/water Form 13 Form 13 EtOH Form 2*Form 2* EtOH/water Form 9 Form 9 IPAc Form 9 Form 9 IPAc/water Form 13Form 13 EA Form 4* Form 4 EA/water Form 4* Form 4* MtBE Form 5* Form 4MtBE/water Form 13 Form 13 IPA Form 6 Form 6 IPA/water Form 6 Form 6 MEKForm 7 Form 7 MEK/water Form 7 Form 7 MA Form 4 Form 4 MA/water Form 12Form 4 n-Propanol Form 4 Form 4** n-Propanol/water Form 9 Form 9 MIBKForm 8 Form 8 MIBK/water Form 13 Form 1 n-Butyl Form 9 Form 9 n-ButylForm 13 Form 1 acetate acetate/water water Form 13 Form 13 Heptane/waterForm 13 Form 1 Heptane Form 13 Form 13 n-Butanol/water Form 13 Form 1n-Butanol Form 9 Form 9 DMSO/water Amorphous Form 10 DMSO Amorphous Form10* DMF/water Form 11 Form 11 DMF Form 11 Form 11* DCM/water Form 13Form 1 DCM Form 13 Form 13

The slurry experiments identified 3 solvated forms from wet samples(Solvates 1, 2, and 3); 2 non-stoichiometric hydrates of Form 1 (Forms12 and 13); and 11 non-solvated forms (Forms 1-11). In some instances,similar XRD scans with minor differences were obtained. These wereconsidered to be part of the same class (e.g., the same form). Forexample, XRD scans of Form 2 and Form 2* were similar and wereconsidered to belong to the same class. The solvated forms were obtainedfrom wet sample analysis; after drying, the sample indicated a differentXRD.

Solvate 1 was obtained from acetone at RT, and after drying, a lowcrystallinity solid was generated. Solvate 2 was obtained from acetone(at RT) and acetone/water (at RT), and after drying, Form 4** wasgenerated. Solvate 3 was obtained from EtOH/water at RT, and afterdrying, Form 2 was generated.

B. Form 1

The experiments that generated Form 1 are shown in Table 6, below. Form1 was generally obtained from drying of Form 13 or Form 12. Form 1 maybe considered as a dehydrated hydrate. Reslurry in many binary solvents(with 5% water) generated Form 1. Purity of the residual solid was98.9%. KF of Form 1 (one sample) solid was 5.8%; residual MeOH of Form 1solid was 0.01%. A TGA scan of fully dried Form 1 solid was performed(FIG. 1C). A 0.33% weight loss was observed before 100° C.

Form 1 showed sharp crystalline peaks on the XRD scan (FIG. 1A). The XRDpeaks of Form 1 are shown in Table 7, below. According to the DSC scan(FIG. 1B), the solid showed a wide endotherm between 50-100° C.; itshowed a sharp exotherm at 281° C.; and the melting point was 363° C.Form 1 has a primitive orthorhombic crystal structure with theapproximate dimensions: a [Å]=29.062, b [Å]=23.945, c [Å]=7.245 and anapproximate volume cell of [Å³/cell]=5,041.7 and a space group definedas Pbca (61).

The Form 1 solid was dried at 75° C. under vacuum overnight, and XRD,DSC, and TGA scans were performed. Comparison of the first and thesecond XRD scans (after drying at 75° C. under vacuum overnight), showedno change. However, the DSC scans indicated the absence of endotherm.The loss of the early peak on the DSC scan had no effect on the XRDtrace, showing that the wide endotherm between 50-100° C. on DSC scanwas due to the free solvent.

The Form 1 solid was heated in a DSC chamber to 305° C. (past theendotherm/exotherm around 280° C.), and then scanned by XRD. Comparisonof the first and the third XRD and DSC scans shows that after heating to305° C., Form 1 converted to Form 9. It can be concluded that theendotherm/exotherm around 280° C. might be due tomelting/crystallization events.

Form 1 tended to convert to a non-stoichiometric or stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water (Form13) at RH above 4050%. The hydrate lost its water below 30% RH. Form 1converts to Form 13 when exposed to air.

The dynamic vapor sorption (DVS) scan of Form 1 solid showed a 17% waterabsorption at 90% RH (FIG. 1D). The XRD data indicated that the solidused in the DVS test converted to the hydrate form before the start ofthe DVS test. However, at 0% RH, water was lost, perhaps indicating thatthe solid was Form 1.

TABLE 6 Summary of experiments that generated Form 1 Form SolventTemperature Wet Dry Form 1 MeOH RT Form 13 Form 1 MeOH 50° C. Form 1Form 1 Toluene RT Form 1 Form 1 Toluene 50° C. Form 1 Form 1 water RTForm 13 Form 1 Heptane RT Form 1 Form 1 DCM RT Form 1 Form 1Acetonitrile/water RT Form 12 Form 1 MeOH/water RT Form 12 Form 1Toluene/water RT Form 13 Form 1 IPAc/water RT Form 13 Form 1 EA/water RTForm 12 Form 1 MtBE/water RT Form 12 Form 1 MA/water RT Form 13 Form 1MIBK/water RT Form 12 Form 1 MIBK/water 50° C. Form 13 Form 1 DCM/waterRT Form 13 Form 1 DCM/water 50° C. Form 13 Form 1 n-Butyl acetate/water50° C. Form 13 Form 1 Heptane/water 50° C. Form 13 Form 1n-Butanol/water 50° C. Form 13 Form 1 *Amount of water in binarysolvents is 5%

TABLE 7 XRD peaks of Form 1 2-Theta d(A) BG Height I % Area I % FWHM5.778 15.2835 57 97 28.3 1765 18.5 0.309 6.801 12.9871 19 343 100 830687.1 0.412 9.26 9.5427 20 178 51.9 3884 40.7 0.371 12.421 7.1203 30 23167.3 4862 51 0.358 13.919 6.357 35 147 42.9 3668 38.5 0.424 14.5016.1033 40 133 38.8 3439 36.1 0.44 16.5 5.3681 47 196 57.1 4286 44.90.372 17.26 5.1333 53 46 13.4 560 5.9 0.207 18.52 4.7868 68 342 99.79539 100 0.474 19.161 4.6282 54 215 62.7 4130 43.3 0.327 20.302 4.370649 133 38.8 2823 29.6 0.361 20.619 4.304 43 80 23.3 2047 21.5 0.43523.056 3.8543 41 38 11.1 765 8 0.342 24.642 3.6098 33 175 51 7235 75.80.703 25.302 3.5171 86 80 23.3 2345 24.6 0.498 26.1 3.4113 83 69 20.11545 16.2 0.381 27.46 3.2453 52 46 13.4 872 9.1 0.322 28.739 3.1038 3984 24.5 2146 22.5 0.434 30.444 2.9337 34 32 9.3 1080 11.3 0.54 33.3022.6882 30 27 7.9 683 7.2 0.405

C. Forms 2, 2*, and 2***

The experiments that generated Forms 2, 2*, and 2** are shown in Table8, below. XRD scans of Forms 2, 2* and 2** were performed (FIGS. 2A, 2D,and 2G show the XRD scans of Forms 2, 2*, and 2**, respectively). TheXRD peaks of Forms 2 and 2* are shown in Tables 9 and 10, below,respectively. DSC scans were also performed (FIGS. 2B, 2E, and 2H showthe DSC scans of Forms 2, 2*, and 2**, respectively). According to theDSC scans, Forms 2, 2* and 2** each showed a wide endotherm between 50°C.-100° C., and multiple endotherms and exotherms before melting at 363°C. The wide endotherm before 100° C. may be due to the containment ofwater/solvent in the solid. Form 2 was obtained from acetonitrile; Form2* from ethanol; Form 2** from n-propanol/5% water.

A TGA scan of Form 2 (FIG. 2C) showed a 2.7% weight loss before 116° C.FIG. 2F shows the TGA scan of Form 2*

A PLM photo of Form 2 was taken, indicating that the particle size ofthis solid was around 50 um.

The Form 2 solid was heated in a DSC machine to 90° C. (past the wideendotherm between 50-100° C.); to 270° C. (past the endotherm/exothermaround 240° C.); and finally to 330° C. (past the exotherm around 330°C.). The residual solid was analyzed by XRD. According to the first andsecond XRD and DSC scans, the form did not change before and afterheating to 90° C. The wide endotherm between 50-100° C. might be freesolvent or hydrate. According to the first and third XRD and DSC scans,after heating a Form 2 sample to 270° C., the solid converted to lowcrystalline solids. According to the first and fourth XRD and DSC scans,after heating the sample to 330° C., the solid converted to Form 9.Thus, the exotherm around 290° C. was a re-crystallization event.According to an XRD and DSC overlay, the behavior of Form 2* was similarto Form 2.

Residual acetonitrile and EtOH in Form 2 and 2* was not detected.

TABLE 8 Summary of experiments that generated Forms 2, 2*, and 2** FormSolvent Temperature Wet Dry Form 2 Acetonitrile RT Form 2 Form 2Acetonitrile 50° C. Form 2* Form 2 EtOH/water RT Solvate 3 Form 2 Form2* EtOH RT Form 2* Form 2* EtOH 50° C. Form 2* Form 2* Acetonitrile 50°C. Form 2* Form 2 Form 2** n- RT Form 2** Form 2** Propanol/water*Amount of water in binary solvents is 5%

TABLE 9 XRD peaks of Form 2 2-Theta d(A) BG Height I % Area I % FWHM7.021 12.5802 164 2202 54.1 36151 38.2 0.279 8.298 10.6462 156 194 4.82332 2.5 0.204 10.399 8.5 193 397 9.8 6246 6.6 0.267 11.258 7.8531 206151 3.7 1407 1.5 0.158 12.239 7.2259 181 287 7 5980 6.3 0.354 14.16.2759 186 648 15.9 14147 15 0.371 14.597 6.0632 195 182 4.5 7983 8.40.746 16.18 5.4734 235 201 4.9 4033 4.3 0.341 16.561 5.3484 251 280 6.98382 8.9 0.509 17.033 5.2013 288 160 3.9 1810 1.9 0.192 17.639 5.0238295 366 9 3542 3.7 0.165 18.878 4.6968 316 1210 29.7 29303 31 0.41219.22 4.614 333 585 14.4 21169 22.4 0.615 19.863 4.4662 340 95 2.3 4370.5 0.078 20.411 4.3474 385 86 2.1 671 0.7 0.133 21.48 4.1335 532 194447.8 61345 64.8 0.536 22.04 4.0297 647 4071 100 94605 100 0.395 23.0363.8576 634 142 3.5 1478 1.6 0.177 24.24 3.6686 497 1688 41.5 28976 30.60.292 25.561 3.482 422 120 2.9 2545 2.7 0.361 25.918 3.4349 365 271 6.711426 12.1 0.717 26.379 3.3759 349 497 12.2 15133 16 0.518 26.739 3.3313387 181 4.4 2845 3 0.267 27.979 3.1863 297 235 5.8 4050 4.3 0.293 29.0433.072 338 347 8.5 4584 4.8 0.225 29.661 3.0094 321 310 7.6 7879 8.30.432 30.204 2.9565 355 135 3.3 1501 1.6 0.189 31.58 2.8308 232 206 5.13991 4.2 0.329 32.602 2.7443 193 63 1.5 1129 1.2 0.305

TABLE 10 XRD peaks of Form 2* 2-Theta d(A) BG Height I % Area I % FWHM4.859 18.1701 127 87 1.2 1714 1.9 0.335 7.119 12.4067 148 3587 48.444853 50.4 0.213 8.321 10.6166 149 407 5.5 4871 5.5 0.203 10.439 8.4669186 1184 16 13629 15.3 0.196 11.319 7.8109 190 413 5.6 4673 5.3 0.19212.3 7.1899 179 1010 13.6 13220 14.9 0.223 12.803 6.9089 182 140 1.91587 1.8 0.193 14.121 6.2667 179 1966 26.5 27290 30.7 0.236 14.5596.0791 199 169 2.3 4381 4.9 0.441 16.236 5.4546 244 436 5.9 5696 6.40.222 16.62 5.3297 271 674 9.1 7919 8.9 0.2 17.059 5.1935 313 629 8.56279 7.1 0.17 17.699 5.0071 303 1094 14.7 12619 14.2 0.196 18.858 4.7018359 2334 31.5 31734 35.7 0.231 19.321 4.5903 325 1650 22.2 28313 31.80.292 19.823 4.4751 412 127 1.7 582 0.7 0.078 20.321 4.3665 327 333 4.53361 3.8 0.172 21.479 4.1336 451 3245 43.8 56365 63.3 0.295 22.1194.0154 612 7417 100 89000 100 0.204 22.782 3.9 536 327 4.4 11890 13.40.618 23.098 3.8475 466 638 8.6 11127 12.5 0.296 24.3 3.6597 361 487365.7 61170 68.7 0.213 25.599 3.4769 487 475 6.4 7278 8.2 0.26 25.883.4399 541 562 7.6 10968 12.3 0.332 26.361 3.3782 372 1289 17.4 2085923.4 0.275 26.739 3.3312 266 660 8.9 13196 14.8 0.34 27.938 3.1909 284560 7.6 9888 11.1 0.3 28.641 3.1142 319 210 2.8 2324 2.6 0.188 29.3983.0357 357 100 1.3 2376 2.7 0.404 29.779 2.9977 295 708 9.5 13168 14.80.316 30.3 2.9473 283 451 6.1 6600 7.4 0.249 31.658 2.8239 239 667 99228 10.4 0.235 32.519 2.7511 221 191 2.6 2896 3.3 0.258 33.903 2.6419213 72 1 876 1 0.207 34.82 2.5744 229 110 1.5 3822 4.3 0.591 35.5042.5264 230 97 1.3 3876 4.4 0.679

D. Form 3

The experiments that generated Form 3 are shown in Table 11, below. XRDand DSC scans of Form 3 were taken (FIGS. 3A and 3B, respectively).Table 12, below, shows the XRD peaks of Form 3. Multiple exotherms andendotherms were observed from the DSC scan of Form 3.

A TGA scan of Form 3 was taken (FIG. 3C) and showed a 1.6% weight lossof the solid before 81° C., followed by a 1.7% weight loss between 81°C. and 169° C.

Form 3 was obtained from IPAc at RT, while Form 3* was obtained fromreslurry in n-butyl acetate.

TABLE 11 Summary of experiments that generated Form 3 and Form 3* FormSolvent Temperature Wet Dry Form 3 IPAc RT Form 3 Form 3 n-Butyl acetateRT Form 3* Form 3 Form 3* n-Butyl acetate RT Form 3* Form 3

TABLE 12 XRD peaks of Form 3 2-Theta d(A) BG Height I % Area I % FWHM5.024 17.5739 231 87 4.4 845 1.9 0.165 6.34 13.9294 368 1030 52.5 1236127.5 0.204 7.219 12.2357 182 1962 100 36491 81.1 0.316 8.441 10.4665 188159 8.1 3261 7.2 0.349 9.237 9.5659 207 320 16.3 3365 7.5 0.179 10.5618.37 240 278 14.2 6270 13.9 0.383 10.998 8.0381 217 849 43.3 17119 38.10.343 11.46 7.715 256 87 4.4 662 1.5 0.129 12.439 7.11 215 311 15.9 650214.5 0.355 12.865 6.8756 209 92 4.7 1599 3.6 0.295 14.22 6.2233 231 52226.6 12265 27.3 0.399 15.524 5.7034 273 311 15.9 2957 6.6 0.162 16.0215.5276 309 218 11.1 2669 5.9 0.208 16.78 5.2792 368 330 16.8 3780 8.40.195 17.181 5.1567 384 99 5 2614 5.8 0.449 17.782 4.9837 428 496 25.36264 13.9 0.215 18.381 4.8227 509 551 28.1 5102 11.3 0.157 19.02 4.6622447 589 30 20513 45.6 0.592 19.758 4.4896 487 423 21.6 14362 31.9 0.57720.8 4.267 520 214 10.9 1518 3.4 0.121 21.19 4.1893 408 418 21.3 458110.2 0.186 21.6 4.1107 553 1017 51.8 41986 93.3 0.702 22.181 4.0044 6621736 88.5 44981 100 0.44 23.185 3.8333 508 259 13.2 3327 7.4 0.218 24.443.6392 467 1441 73.4 29510 65.6 0.348 25.198 3.5313 551 232 11.8 1362 30.1 25.618 3.4745 557 79 4 365 0.8 0.079 26.103 3.4109 512 180 9.2 737416.4 0.696 26.479 3.3634 475 306 15.6 11652 25.9 0.647 27.3 3.264 455133 6.8 1016 2.3 0.13 28.04 3.1796 378 93 4.7 1485 3.3 0.271 28.823.0953 372 201 10.2 3455 7.7 0.292 29.258 3.0499 362 76 3.9 2580 5.70.577 29.88 2.9878 334 191 9.7 4011 8.9 0.357 31.802 2.8115 251 205 10.44094 9.1 0.34 32.62 2.7429 231 87 4.4 1109 2.5 0.217 32.943 2.7167 21552 2.7 1107 2.5 0.362 33.961 2.6375 217 101 5.1 1686 3.7 0.284

E. Form 4

The experiments that generated Forms 4, 4*, and 4** are shown in Table13, below. XRD of Forms 4, 4*, and 4** were taken (FIGS. 4A, 4D, and 4G,respectively). Tables 14 and 15, below, show the XRD peaks of Form 4 andForm 4*, respectively. DSC scans of Forms 4, 4*, and 4** were alsoperformed (FIGS. 4B, 4E, and 4H, respectively). According to the DSCscans, Form 4 showed a wide endotherm between 50° C.-100° C., followedby multiple endotherms/exotherms, and then melted at around 367° C.Forms 4* and 4** showed similar DSC patterns as Form 4.

TGA scans of Form 4, Form 4*, and Form 4** were taken (FIGS. 4C, 4F, and4I, respectively). For Form 4, there was an 8.3% weight loss before 200°C.; for Form 4*, there was a 4.4% weight loss before 102° C., followedby a 0.5% weight loss between 102° C. and 250° C.; and for Form 4**,there were three stages of weight loss, which were 2.8%, 1.9%, and 1.3%,respectively.

These solid forms were obtained from methyl acetate, n-propanol, MIBK,MtBE, ethyl acetate, acetone/water, and ethyl acetate/water.

TABLE 13 Summary of experiments that generated Forms 4, 4*, and 4** FormSolvent Temperature Wet Dry Form 4 EA RT Form 4* Form 4 EA 50° C. Form4* Form 4 MA RT Form 4 Form 4 MA 50° C. Form 4 Form 4 MA/water 50° C.Form 12 Form 4 MtBE 50° C. Form 5* Form 4 n-Propanol RT Form 4 Form 4*Form 4* EA RT Form 4* Form 4* EA 50° C. Form 4* Form 4 EA/water 50° C.Form 4* Form 4* n-Propanol RT Form 4 Form 4* Form 4** Acetone/water RTSolvate 2 Form 4** Acetone 50° C. Solvate 2 Form 4** n-Propanol 50° C.Form 4 Form 4** Acetone/water 50° C. Form 4** Form 4** *Amount of waterin binary solvents is 5%

TABLE 14 XRD peaks of Form 4 2-Theta d(A) BG Height I % Area I % FWHM3.433 25.7129 197 48 1 697 0.7 0.247 7.019 12.5829 222 3897 77.3 6696869.4 0.292 8.659 10.203 242 448 8.9 8198 8.5 0.311 8.98 9.8395 223 2194.3 7649 7.9 0.594 9.64 9.1672 251 516 10.2 6969 7.2 0.23 10.917 8.0978210 77 1.5 1041 1.1 0.23 12.339 7.1673 220 465 9.2 9572 9.9 0.35 13.826.4023 268 501 9.9 11493 11.9 0.39 14.278 6.1981 271 192 3.8 7288 7.60.645 14.923 5.9314 288 172 3.4 1636 1.7 0.162 16.462 5.3804 310 329 6.53066 3.2 0.158 17.041 5.199 375 105 2.1 942 1 0.153 17.638 5.0241 4351073 21.3 13511 14 0.214 18.281 4.8488 487 772 15.3 9782 10.1 0.21519.52 4.5437 504 1590 31.5 31949 33.1 0.342 21.759 4.081 677 5040 10096504 100 0.326 23.22 3.8275 693 1457 28.9 28109 29.1 0.328 25.12 3.5421710 3091 61.3 69330 71.8 0.381 25.76 3.4556 455 827 16.4 22029 22.80.453 27.221 3.2733 419 180 3.6 2915 3 0.275 28.638 3.1145 409 210 4.24338 4.5 0.351 29.259 3.0498 461 568 11.3 11998 12.4 0.359 30.137 2.9629409 149 3 1946 2 0.222 31.817 2.8102 253 110 2.2 4034 4.2 0.623 32.3192.7677 245 137 2.7 3829 4 0.475

TABLE 15 XRD peaks of Form 4* 2-Theta d(A) BG Height I % Area I % FWHM4.981 17.7282 270 684 15.8 12231 12.6 0.304 7.22 12.2329 244 3416 7965744 67.8 0.327 8.459 10.4447 202 335 7.7 4814 5 0.244 10.56 8.3707 219629 14.5 10739 11.1 0.29 11.42 7.7419 240 203 4.7 2908 3 0.244 12.427.1209 221 614 14.2 11445 11.8 0.317 13.019 6.7947 238 59 1.4 423 0.40.122 14.26 6.2057 227 1052 24.3 20787 21.4 0.336 16.318 5.4274 409 85 2665 0.7 0.133 16.722 5.2973 332 496 11.5 8980 9.3 0.308 17.199 5.1515393 226 5.2 3448 3.6 0.259 17.82 4.9733 402 725 16.8 8502 8.8 0.19918.98 4.672 432 1352 31.3 36895 38.1 0.464 19.44 4.5623 439 990 22.928546 29.4 0.49 20.46 4.3371 444 119 2.8 1163 1.2 0.166 21.58 4.1144 4581982 45.8 71568 73.8 0.614 22.22 3.9974 837 4325 100 96937 100 0.38123.16 3.8373 758 114 2.6 1085 1.1 0.162 24.42 3.6421 522 2466 57 4897750.5 0.338 25.679 3.4663 590 252 5.8 5211 5.4 0.352 26.5 3.3607 470 67115.5 23177 23.9 0.587 26.95 3.3056 356 313 7.2 3645 3.8 0.198 28.1183.1709 385 255 5.9 5045 5.2 0.336 29.9 2.9858 360 383 8.9 13112 13.50.582 30.421 2.9359 346 239 5.5 5602 5.8 0.398 31.779 2.8134 293 336 7.85905 6.1 0.299 32.618 2.743 267 124 2.9 1934 2 0.265

F. Forms 5 and 5*

The experiments that generated Forms 5 and 5* are shown in Table 16,below. XRD scans of Forms 5 and 5* were taken (FIGS. 5A and 5D,respectively). The XRD peaks of Form 5 are shown in Table 17, below. ADSC scan of Form 5 was also performed and showed a wide endothermbetween 50° C.-100° C., and multiple endotherms and exotherms beforemelting at 363° C. (FIG. 5B).

A TGA scan of Form 5 solid showed a 3.1% weight loss before 100° C.,followed by a 1.7% weight loss between 100° C. and 250° C. (FIG. 5C).

Forms 5 and 5* were obtained from slurrying Form 12 in MtBE at RT and50° C. Wet solid showed Form 5*, while dry solid indicated Form 5.

TABLE 16 Summary of experiments that generated Forms 5 and 5* FormSolvent Temperature Wet Dry Form 5 MtBE RT Form 5* Form 5 Form 5* MtBERT Form 5* Form 5 MtBE 50° C. Form 5* Form 4

TABLE 17 XRD peaks of Form 5 2-Theta d(A) BG Height I % Area I % FWHM5.098 17.3185 260 155 2.4 2464 2.1 0.27 6.38 13.8428 256 1778 27.7 3473329.6 0.332 7.28 12.1332 214 3964 61.6 78158 66.5 0.335 8.518 10.3715 234241 3.7 3170 2.7 0.224 9.24 9.5627 227 472 7.3 6614 5.6 0.238 10.6398.3083 266 765 11.9 20508 17.5 0.456 11.019 8.0226 242 1596 24.8 3762032 0.401 11.483 7.6998 398 133 2.1 949 0.8 0.121 12.44 7.1091 246 5849.1 11910 10.1 0.347 12.94 6.8358 249 152 2.4 4189 3.6 0.469 14.3016.1883 279 1114 17.3 22226 18.9 0.339 14.839 5.9648 300 167 2.6 5989 5.10.61 15.581 5.6827 404 376 5.8 4045 3.4 0.183 16.08 5.5073 452 459 7.19013 7.7 0.334 16.357 5.4146 509 260 4 11967 10.2 0.782 16.839 5.2606521 473 7.4 7195 6.1 0.259 17.254 5.1351 550 258 4 4373 3.7 0.288 17.8394.968 562 414 6.4 4207 3.6 0.173 18.439 4.8078 667 590 9.2 5946 5.10.171 19.059 4.6527 616 1603 24.9 35964 30.6 0.381 19.5 4.5486 671 116318.1 30384 25.9 0.444 20.882 4.2506 850 305 4.7 2860 2.4 0.159 21.6794.0959 935 2272 35.3 66194 56.4 0.495 22.28 3.9867 1083 6430 100 117449100 0.311 23.221 3.8273 856 564 8.8 9429 8 0.284 24.461 3.6361 697 425066.1 74709 63.6 0.299 25.276 3.5206 726 170 2.6 1349 1.1 0.135 26.0813.4137 756 442 6.9 17518 14.9 0.674 26.52 3.3582 689 1014 15.8 3461529.5 0.58 28.139 3.1686 528 306 4.8 4846 4.1 0.269 28.821 3.0952 533 4637.2 7067 6 0.259 29.94 2.9819 499 755 11.7 15565 13.3 0.35 30.458 2.9324435 467 7.3 9861 8.4 0.359 31.86 2.8065 343 648 10.1 13697 11.7 0.35932.642 2.741 314 125 1.9 2403 2 0.327 34.002 2.6344 298 123 1.9 1956 1.70.27

G. Form 6

The experiments that generated Form 6 are shown in Table 18, below. XRDand DSC scans of Form 6 were taken (FIGS. 6A and 6B, respectively).According to the DSC scan, the solid showed a small exotherm at 250° C.and a sharp melting endotherm at 358° C.

Form 6 was obtained by slurrying starting material in IPA and IPA/5%water at RT and 50° C.

TABLE 18 Summary of experiments that generated Form 6 Form SolventTemperature Wet Dry Form 6 IPA RT Form 6 Form 6 IPA 50° C. Form 6 Form 6IPA/water RT Form 6 Form 6 IPA/water 50° C. Form 6 Form 6 *Amount ofwater in binary solvents is 5%

H. Form 7

The experiments that generated Form 7 are shown in Table 19, below. XRDand DSC scans of Form 7 were taken (FIGS. 7A and 7B, respectively). TheXRD peaks of Form 7 are shown in Table 20, below. According to the DSCscan, the solid showed two exotherms at 227° C. and 299° C., followed bya melting endotherm at 365° C. Form 7 showed low degree of crystallinityon XRD. The double exotherm on the DSC scans may be associated with thelow crystallinity observed on the XRD scan.

A TGA scan of Form 7 solid showed a 12% weight loss before 200° C. (FIG.7C).

Form 7 was obtained from MEK and MEK/5% water at RT and 50° C.

TABLE 19 Summary of experiments that generated Form 7 Form SolventTemperature Wet Dry Form 7 MEK RT Form 7 Form 7 MEK 50° C. Form 7 Form 7MEK/water RT Form 7 Form 7 MEK/water 50° C. Form 7 Form 7 *Amount ofwater in binary solvents is 5%

TABLE 20 XRD peaks of Form 7 2-Theta d(A) BG Height I % Area I % FWHM4.94 17.8745 362 1384 23.3 50829 29.2 0.624 7.06 12.5111 286 3171 53.369159 39.8 0.371 8.759 10.0876 370 628 10.6 9606 5.5 0.26 9.9 8.9272 429537 9 11110 6.4 0.352 10.881 8.1241 546 879 14.8 16425 9.4 0.318 11.847.4681 588 413 6.9 7187 4.1 0.296 12.997 6.8061 463 135 2.3 1351 0.80.17 14.404 6.1442 604 126 2.1 3331 1.9 0.449 15.1 5.8626 791 596 108819 5.1 0.252 15.92 5.5622 792 593 10 24460 14.1 0.701 16.581 5.3421739 641 10.8 14919 8.6 0.396 18.5 4.7919 1066 1555 26.1 43174 24.8 0.47219.4 4.5717 1087 930 15.6 17521 10.1 0.32 20.382 4.3535 1178 154 2.6 8670.5 0.096 21.56 4.1183 1424 5949 100 173972 100 0.497 22.098 4.0192 1830692 11.6 17678 10.2 0.434 23.22 3.8275 1749 1971 33.1 42151 24.2 0.36424.203 3.6743 1776 351 5.9 11935 6.9 0.578 24.884 3.5751 1658 271 4.62378 1.4 0.149 25.759 3.4556 1416 492 8.3 19894 11.4 0.687 26.3 3.38581335 499 8.4 23631 13.6 0.805 27.34 3.2594 1192 307 5.2 4494 2.6 0.24928.641 3.1142 1004 382 6.4 18030 10.4 0.802 29.078 3.0684 979 324 5.414234 8.2 0.747 30.28 2.9492 759 711 12 16004 9.2 0.383 31.985 2.7959551 111 1.9 4816 2.8 0.738 33.402 2.6804 509 102 1.7 2060 1.2 0.34334.24 2.6167 474 92 1.5 1901 1.1 0.351

I. Form 8

The experiments that generated Form 8 are shown in Table 21, below. XRDand DSC scans of Form 8 were taken (FIGS. 8A and 8B, respectively). TheXRD peaks of Form 8 are shown in Table 22, below. According to the DSCscan, the solid showed two endotherms at 205° C. and 231° C., followedby an exotherm at 279° C., followed by a melting endotherm at 362° C.Form 8 showed a low degree of crystallinity on the XRD scan. The doubleexotherm on the DSC scan may confirm the low crystallinity seen on XRD(low crystalline material convert to higher crystallinity solid).

A TGA scan of Form 8 showed a 4.2% weight loss before 190° C., followedby a 3.9% weight loss between 190° C. and 261° C. (FIG. 8C).

Form 8 was obtained from MIBK at RT and 50° C. MIBK/5% water reslurrydoes not produce the same form.

TABLE 21 Summary of experiments that generated Form 8 Form SolventTemperature Wet Dry Form 8 MIBK RT Form 8 Form 8 MIBK 50° C. Form 8 Form8

TABLE 22 XRD peaks of Form 8 2-Theta d(A) BG Height I % Area I % FWHM6.88 12.8368 318 2815 80.8 71578 51.7 0.432 10.699 8.2619 380 70 2 7220.5 0.175 11.48 7.7016 344 466 13.4 9513 6.9 0.347 12.66 6.9866 348 1363.9 1759 1.3 0.22 14.16 6.2496 435 166 4.8 3298 2.4 0.338 15.259 5.8017483 269 7.7 6267 4.5 0.396 16.879 5.2484 669 333 9.6 7638 5.5 0.3917.681 5.0121 780 1959 56.2 76035 54.9 0.66 19.618 4.5213 833 134 3.82110 1.5 0.268 21.5 4.1296 1116 3484 100 138450 100 0.676 24.244 3.6682899 99 2.8 2643 1.9 0.454 27.559 3.234 753 366 10.5 11182 8.1 0.51928.881 3.0889 636 279 8 8137 5.9 0.496 30.878 2.8935 403 87 2.5 1890 1.40.369 31.221 2.8624 386 69 2 1898 1.4 0.468

J. Form 9

The experiments that generated Form 9 are shown in Table 23, below. XRDand DSC scans of Form 9 were taken (FIGS. 9A and 9B, respectively). TheXRD peaks of Form 9 are shown in Table 24, below. According to the DSCscan, the solid showed a single melting endotherm at 364° C. Form 9 hasa primitive monoclinic crystal structure with the approximatedimensions: a [Å]=17.135, b [Å]=14.342, c [Å]=10.186; α(deg)=90,β(deg)=95.99, γ(deg)=90 and an approximate volume cell of[Å³/cell]=2,489.5 and a space group defined as P2₁/c (14).

A TGA scan of Form 9 showed a 0.28% weight loss before 100° C. (FIG.9C).

Other forms, when heated to just before melting at 364° C., seemed toconvert to Form 9. This has been confirmed for Forms 1 and 2.

A DVS scan of Form 9 showed a 0.8% water absorption at 90% RH. Form 9did not change its form before and after the DVS scan (FIG. 9D).

TABLE 23 Summary of experiments that generated Form 9 Form SolventTemperature Wet Dry n-Butanol RT Form 9 Form 9 Form 9 IPAc 50° C. Form 9Form 9 n-Butyl acetate 50° C. Form 9 Form 9 n-Butanol 50° C. Form 9 Form9 EtOH/water 50° C. Form 9 Form 9 n- 50° C. Form 9 Form 9 Propanol/water*Amount of water in binary solvents is 5%

TABLE 24 XRD peaks of Form 9 2-Theta d(A) BG Height I % Area I % FWHM4.94 17.8746 21 895 100 23398 100 0.444 6.26 14.1076 21 34 3.8 513 2.20.257 10.099 8.7516 28 66 7.4 1172 5 0.302 11.883 7.4413 30 46 5.1 8283.5 0.306 13.16 6.7221 27 37 4.1 400 1.7 0.184 15.341 5.771 39 71 7.91541 6.6 0.369 16.518 5.3622 40 93 10.4 1728 7.4 0.316 18.622 4.7608 46260 29.1 7069 30.2 0.462 19.74 4.4938 80 138 15.4 1937 8.3 0.239 21.1014.2068 64 342 38.2 8314 35.5 0.413 22.42 3.9622 56 77 8.6 1721 7.4 0.3824.1 3.6897 58 198 22.1 3904 16.7 0.335 25.2 3.5311 63 157 17.5 361515.5 0.391 26.897 3.312 46 44 4.9 1307 5.6 0.505 28.577 3.121 35 54 61754 7.5 0.552 29.884 2.9874 32 30 3.4 477 2 0.254 30.926 2.8891 35 323.6 682 2.9 0.341

K. Forms 10 and 10*

The experiments that generated Forms 10 and 10* are shown in Table 25,below. XRD scans of Forms 10 and 10* were taken (FIGS. 10A and 10D,respectively). The XRD peaks of Form 10 are shown in Table 26, below.DSC scans of Forms 10 and 10* were also taken and indicated multipleendotherms/exotherms, followed by melting at 367° C. (FIGS. 10B and 10E,respectively).

Forms 10 and 10* were produced by drying of amorphous solids (obtainedfrom DMSO and DMSO/water reslurry at RT and 50° C.). Both Form 10 and10* are associated with DMSO.

A TGA scan of Form 10 solid showed a 0.6% weight loss before 100° C.,followed by a 3.8% weight loss between 100° C. and 170° C., followed bya 7.1% weight loss between 170° C. and 260° C. (FIG. 10C).

TABLE 25 Summary of experiments that generated Forms 10 and 10* FormSolvent Temperature Wet Dry Form 10 DMSO RT amorphous Form 10 DMSO/waterRT amorphous Form 10 DMSO/water 50° C. amorphous Form 10 Form 10* DMSO50° C. amorphous Form 10* *Amount of water in binary solvents is 5%

TABLE 26 XRD peaks of Form 10 2-Theta d(A) BG Height I % Area I % FWHM6.701 13.1792 148 1553 32.1 31364 34.4 0.343 8.3 10.6444 207 1026 21.217914 19.6 0.297 9.38 9.4203 212 1352 27.9 21528 23.6 0.271 10.8198.1705 223 514 10.6 8714 9.6 0.288 11.919 7.4192 271 635 13.1 9435 10.30.253 12.919 6.8469 266 1160 24 22094 24.2 0.324 13.718 6.45 242 81 1.7856 0.9 0.18 14.84 5.9646 271 244 5 4716 5.2 0.329 15.536 5.6988 312 1473 1304 1.4 0.151 16.58 5.3424 392 1813 37.5 30451 33.4 0.286 17.8214.9731 434 2208 45.6 58342 64 0.449 18.16 4.881 434 2862 59.2 89029 97.60.529 19.001 4.6667 1021 3215 66.5 45840 50.2 0.242 19.88 4.4623 11631454 30.1 19014 20.8 0.222 20.701 4.2873 1514 4838 100 78140 85.7 0.27521.66 4.0994 596 4067 84.1 91229 100 0.381 23.38 3.8017 596 2251 46.564928 71.2 0.49 24.22 3.6717 663 4578 94.6 84228 92.3 0.313 26 3.4242595 430 8.9 11172 12.2 0.442 27.12 3.2853 639 146 3 1986 2.2 0.231 27.883.1974 642 2073 42.8 48132 52.8 0.395 28.88 3.089 638 477 9.9 14155 15.50.504 29.867 2.9891 544 205 4.2 4572 5 0.379 30.32 2.9454 528 568 11.711936 13.1 0.357 31.098 2.8735 517 443 9.2 5841 6.4 0.224 31.661 2.8236433 118 2.4 953 1 0.137 33.379 2.6822 433 311 6.4 9235 10.1 0.505 34.222.6181 444 281 5.8 6059 6.6 0.367 34.822 2.5743 460 84 1.7 2707 3 0.54835.438 2.5309 465 89 1.8 858 0.9 0.164

L. Forms 11 and 11*

The experiments that generated Forms 11 and 11* are shown in Table 27,below. XRD scans of Forms 11 and 11* were taken (FIGS. 11A and 11D,respectively). The XRD peaks of Form 11 and Form 11* are shown in Tables28 and 29, below, respectively. DSC scans of Forms 11 and 11* were alsotaken (FIGS. 11B and 11E, respectively). According to the DSC scans, thesolid showed multiple endotherms/exotherms and eventually melted at 368°C. Amorphous halo was observed in the XRD of both Forms. The doubleexotherm on the DSC of both forms may be also associated with theamorphous halo observed on XRD scans.

TGA scans of Form 11 and 11* were taken (FIGS. 11C and 11F,respectively). Form 11 solids showed a 0.8% weight loss before 100° C.,followed by a 7.0% weight loss between 100° C. and 249° C. Form 11*solids showed a 1.0% weight loss before 100° C., and followed by a 7.0%weight loss before 250° C.

Forms 11 and 11* were obtained from DMF and DMF/5% water at RT and 50°C.

TABLE 27 Summary of experiments that generated Forms 11 and 11* FormSolvent Temperature Wet Dry Form 11 DMF RT Form 11 Form 11 DMF 50° C.Form 11 Form 11* DMF/water RT Form 11 Form 11 DMF/water 50° C. Form 11Form 11 Form 11* DMF 50° C. Form 11 Form 11* *Amount of water in binarysolvents is 5%

TABLE 28 XRD peaks of Form 11 2-Theta d(A) BG Height I % Area I % FWHM6.42 13.7554 19 496 81.7 9502 100 0.326 8.421 10.4908 20 335 55.2 577560.8 0.293 8.86 9.9726 24 166 27.3 4268 44.9 0.437 10.859 8.1404 21 9115 1292 13.6 0.241 12.479 7.0871 44 83 13.7 1004 10.6 0.206 12.9776.8165 29 51 8.4 1542 16.2 0.514 14.519 6.0957 28 91 15 1421 15 0.26516.801 5.2727 57 104 17.1 2226 23.4 0.364 17.801 4.9787 103 358 59 510953.8 0.243 18.519 4.7871 101 607 100 8460 89 0.237 18.861 4.7011 102 12520.6 1763 18.6 0.24 19.922 4.453 85 383 63.1 7376 77.6 0.327 20.258 4.3879 180 29.7 5778 60.8 0.546 20.899 4.247 76 105 17.3 1291 13.6 0.20921.738 4.085 86 55 9.1 757 8 0.234 22.441 3.9585 94 471 77.6 7125 750.257 22.859 3.8871 78 167 27.5 3724 39.2 0.379 24.458 3.6365 60 29849.1 4544 47.8 0.259 26.82 3.3213 45 195 32.1 4777 50.3 0.416 29 3.076443 99 16.3 3112 32.8 0.534 29.524 3.023 63 37 6.1 190 2 0.087 31.042.8788 38 46 7.6 826 8.7 0.305 31.825 2.8095 36 56 9.2 737 7.8 0.22432.456 2.7563 31 40 6.6 857 9 0.364

TABLE 29 XRD peaks of Form 11* 2-Theta d(A) BG Height I % Area I % FWHM6.441 13.7116 24 424 93.4 8643 100 0.347 6.944 12.7196 20 84 18.5 207824 0.421 8.518 10.3718 22 227 50 4871 56.4 0.365 8.86 9.9721 23 147 32.43581 41.4 0.414 10.859 8.141 26 107 23.6 1695 19.6 0.269 12.519 7.064834 90 19.8 2165 25 0.409 13.021 6.7935 31 54 11.9 1517 17.6 0.478 14.6186.0547 32 76 16.7 1605 18.6 0.359 16.638 5.3238 55 115 25.3 2410 27.90.356 17.838 4.9684 71 368 81.1 6709 77.6 0.31 18.522 4.7864 130 454 1007473 86.5 0.28 19.96 4.4447 109 315 69.4 6433 74.4 0.347 20.26 4.3795109 146 32.2 5359 62 0.624 20.904 4.2461 127 58 12.8 559 6.5 0.16421.639 4.1034 142 194 42.7 4690 54.3 0.411 22.441 3.9586 161 368 81.15409 62.6 0.25 22.94 3.8735 78 150 33 6057 70.1 0.686 23.398 3.7988 78116 25.6 2330 27 0.341 24.44 3.6391 75 305 67.2 5097 59 0.284 26.8193.3215 68 206 45.4 4795 55.5 0.396 29.018 3.0745 56 109 24 4093 47.40.638 29.566 3.0188 82 43 9.5 341 3.9 0.135 31.022 2.8804 58 55 12.1 5095.9 0.157 31.881 2.8047 49 48 10.6 482 5.6 0.171 32.338 2.7661 42 50 111360 15.7 0.462

Additional experiments with Form 1 of a compound of Formula (I) showedthat when Form 1 was exposed to moisture (FIGS. 15A-15D), Form 1 formednon-stoichiometric or stoichiometric hydrates. The crystal lattice ofForm 1 expanded when water was sorbed, giving rise to XRD peaks at ˜5,˜7 and ˜11 degrees while maintaining the main XRD pattern. The hydratesof Form 1 of a compound of Formula (I) (Form 11) were fully reversible,and lost water when exposed to % RH of less than 20%, turning Form 11 tohydrated forms of Form 1 and to the anhydrous Form 1.

M. Form 13 and Form 12

The experiments that generated Form 13 and Form 12 are shown in Tables30 and 32, below, respectively. Forms 12 and 13 are examples ofnon-stoichiometric hydrates of Form 1 that have between 1% and about 20%by weight water. XRD scans of Form 13 and Form 12 were taken (FIGS. 13Aand 12A, respectively). The XRD peaks of Form 13 are shown in Table 31,below. DSC scans of Form 13 and Form 12 were also taken (FIGS. 13B and12B, respectively). According to the DSC scan, Form 13 solids showed awide endotherm between 50° C.-100° C., followed by a small exotherm at278° C.; and a melting endotherm at 363° C. According to the DSC scan,Form 12 solids showed a wide endotherm between 50° C.-100° C., followedby a sharp exotherm at 283° C.; and a melting endotherm at 364° C.

The purity of the Form 13 sample was 98.8%; the KF of an undried Form 13sample was 35.7%. A DVS scan of Form 13 solid showed a 17% watersorption at 90% RH (FIG. 13D). Form 13 converted to Form 1 upon drying.

A TGA scan of Form 13 solid showed a 1.9% weight loss before 100° C.(FIG. 13C).

Form 13 solid was heated in a DSC chamber to 170° C. (past the endothermbetween 50-100° C.), and then scanned by XRD. A comparison of the firstand the second XRD and DSC scans, after heating to 170° C., showed thatForm 13 converted to Form 1. It can be concluded that the endothermbetween 50-100° C. is due to bonded water.

Form 13 has a primitive orthorhombic crystal structure with theapproximate dimensions: a [Å]=33.759, b [Å]=22.590, c [Å]=7.386 and anapproximate volume cell of [Å³/cell]=5,632.5 and a space group definedas Pbca(61).

Form 13 solid was heated in a DSC chamber to 330° C. (past theendotherm/exotherm around 300° C.), and then scanned by XRD. Acomparison of the first and the third XRD and DSC scans, after heatingto 170° C., showed that Form 13 converted to Form 9. It can be concludedthat the endotherm/exotherm is due to melting/crystallization events.

TABLE 30 Summary of experiments that generated Form 13 Form SolventTemperature Wet Dry Form 13 MeOH RT Form 13 Form 1 MeOH/water 50° C.Form 13 Form 13 water RT Form 13 Form 1 water 50° C. Form 13 Form 13Toluene/water RT Form 13 Form 1 Toluene/water 50° C. Form 13 Form 13MA/water RT Form 13 Form 1 n-Butyl RT Form 13 Form 12 acetate/watern-Butyl 50° C. Form 13 Form 1 acetate/water Heptane 50° C. Form 13 Form13 Heptane/water RT Form 13 Form 12 Heptane/water 50° C. Form 13 Form 1n-Butanol/water RT Form 13 Form 13 n-Butanol/water 50° C. Form 13 Form 1DCM 50° C. Form 13 Form 13 DCM/water RT Form 13 Form 1 DCM/water 50° C.Form 13 Form 1 Acetonitrile/water 50° C. Form 13 Form 13 IPAc/water 50°C. Form 13 Form 13 MtBE/water 50° C. Form 13 Form 13 MIBK/water 50° C.Form 13 Form 1 *Amount of water in binary solvents is 5%

TABLE 31 XRD peaks of Form 13 2-Theta d(A) BG Height I % Area I % FWHM5.06 17.45 278 309 6.5 3685 4.8 0.203 6.379 13.8451 223 4743 100 76110100 0.273 9.24 9.5632 164 1370 28.9 20018 26.3 0.248 11 8.0364 173 344572.6 51777 68 0.256 12.899 6.8574 195 173 3.6 3114 4.1 0.306 13.4626.572 199 204 4.3 2376 3.1 0.198 14.159 6.2498 202 390 8.2 5424 7.10.236 15.56 5.6901 262 1335 28.1 19295 25.4 0.246 16.059 5.5145 302 100221.1 17561 23.1 0.298 16.841 5.26 313 774 16.3 7797 10.2 0.171 17.465.075 322 314 6.6 3863 5.1 0.209 18.419 4.8128 339 2354 49.6 29374 38.60.212 19.3 4.5951 357 210 4.4 8112 10.7 0.657 19.741 4.4935 329 1566 3330236 39.7 0.328 20.202 4.3919 342 210 4.4 2880 3.8 0.233 20.84 4.2589300 1054 22.2 18033 23.7 0.291 21.201 4.1873 284 964 20.3 15700 20.60.277 22.121 4.015 259 197 4.2 2208 2.9 0.191 23.2 3.8307 268 482 10.27844 10.3 0.277 24.42 3.642 280 1101 23.2 16244 21.3 0.251 24.839 3.5816303 468 9.9 9306 12.2 0.338 25.219 3.5284 385 1093 23 16646 21.9 0.25926.164 3.4032 359 357 7.5 5064 6.7 0.241 26.499 3.3609 402 317 6.7 73169.6 0.392 26.798 3.324 346 179 3.8 8025 10.5 0.762 27.339 3.2594 394 72015.2 13063 17.2 0.308 27.639 3.2247 341 318 6.7 5673 7.5 0.303 28.7993.0974 256 805 17 16756 22 0.354 29.902 2.9857 262 234 4.9 3508 4.60.255 31.234 2.8613 230 106 2.2 1473 1.9 0.236 31.96 2.798 226 308 6.53908 5.1 0.216 32.939 2.717 208 117 2.5 1444 1.9 0.21 33.962 2.6375 199266 5.6 4617 6.1 0.295 34.917 2.5675 217 73 1.5 736 1 0.171

TABLE 32 Summary of experiments that generated Form 12 Form SolventTemperature Wet Dry Form 12 Acetonitrile/water RT Form 12 Form 1MeOH/water RT Form 12 Form 1 IPAc/water RT Form 12 Form 1 EA/water RTForm 12 Form 1 MtBE/water RT Form 12 Form 1 MIBK/water RT Form 12 Form 1n-Butyl RT Form 13 Form 12 acetate/water Heptane/water RT Form 13 Form12 MA/water 50° C. Form 12 Form 4 *Amount of water in binary solvents is5%

N. Solvates 1-3

The experiments that generated Solvates 1, 2, and 3 are shown in Table33, below. Solvates 1 and 2 solids were exposed to air overnight, andthen analyzed by XRD. After the analysis, the solids were dried at 50°C. under vacuum, and then analyzed by XRD again.

After exposure to air overnight, Solvate 1 converted to lowcrystallinity; after drying at 50° C., the sample was still lowcrystallinity solid. After exposure to air overnight, the XRD pattern ofSolvate 2 changed a little; after drying at 50° C., the form remainedthe same as the solid exposed to air overnight.

TABLE 33 Summary of experiments that generated solvates 1-3 Form SolventTemperature Wet Dry Solvate 1 Acetone RT Solvate 1 Low crystallinitySolvate 2 Acetone/water RT Solvate 2 Form 4** Acetone 50° C. Solvate 2Form 4** Solvate 3 EtOH/water RT Solvate 3 Form 2 *Amount of water inbinary solvent is 5%

Example 2: Competitive Slurry Experiments Between Polymorph Forms

In order to find out the thermodynamic stability between the differentforms, several competitive slurry experiments were carried out. Form 1,Form 2, Form 2*, Form 3, Form 4, Form 4*, Form 4**, Form 5, Form 7, Form8, Form 9, Form 10, Form 11, Form 11*, and Form 13 (10 mg for each) wasmixed and slurried in 2 mL of solvent at both RT and 50° C. The solidswere slurried for 3-5 days and then analyzed by XRD. According to theanalytical data, Form 2* was the most stable form in a MeOH, EtOH, andacetone system at both RT and 50° C. Form 4 or 4* was most stable in EAat RT and 50° C. Form 13 was most stable in water at RT and 50° C. Table34 shows the XRD scan results from the competitive slurry experiments.

TABLE 34 XRD scan results of competitive slurry experiments Form after 3days; Temperature Solvent wet/dry Form after 5 days; wet/dry RT MeOHForm 2*/Form 2* Form 2*/Form 2* EtOH Form 2*/Form 2* Form 2*/Form 2*Acetone Form 2*/Form 2* Form 2*/Form 2* EA Form 4/Form 4 Form 4/Form 4water Form 13/Form 13 Form 13/Form 1&Form 13 50° C. MeOH Form 2*/Form 2*Form 2*/Form 2* EtOH Form 2*/Form 2* Form 2*/Form 2* Acetone Form2*/Form 2* Form 2*/Form 2* EA Form 4/Form 4 Form 4*/Form 4* water Form13/Form 13 Form 13/Form 13

In order to find out the thermodynamic stability between Form 13 andForm 9, several competitive slurry experiments were carried out. 15 mgof Form 1, Form 9 and Form 13 solid were mixed in 1 mL of toluene, IPAc,and n-butyl acetate, and slurried for 3 days at RT and 50° C.

The residual solid was analyzed by XRD. After a three-day slurry, it wasdifficult to tell which one was more stable between Form 13 and Form 9.The XRD scan results of the experiment is shown in Table 35, below.

TABLE 35 XRD scan results competitive slurry experiments TemperatureSolvent Form after 3 days; wet/dry RT Toluene Form 13/Form 1 IPAc Form9 + Form 13/Form 9 + Form 1 n-Butyl acetate Form 9 + Form 13/Form 9 +Form 1 50° C. Toluene Form 9 + Form 13/Form 9 + Form 1 IPAc Form 9/Form9 n-Butyl acetate Form 9 + Form 13/Form 9 + Form 1

OTHER EMBODIMENTS

It is to be understood that the foregoing description is intended toillustrate and not limit the scope of the disclosure, which is definedby the scope of the appended claims. Other aspects, advantages, andmodifications are within the scope of the following claims.

What is claimed is:
 1. A method of treating osteoarthritis in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a single-dose, ready-to-useformulation comprising a compound of Formula (I)

wherein the compound of Formula (I) is present as: polymorph Form 1having an X-ray powder diffraction pattern comprising peaks at ° 2θvalues of 6.8±0.2, 12.4±0.2, and 18.5±0.2; and polymorph Form 9 havingan X-ray powder diffraction pattern comprising peaks at ° 2θ values of4.9±0.2, 18.6±0.2, and 21.1±0.2, wherein the compound comprises no morethan about 5% by weight of polymorph Form 9; wherein the compound ofFormula (I) is prepared by a process comprising: (a) providing anaqueous solution comprising water; (b) providing a slurry comprising acompound of Formula (I); (c) mixing the aqueous solution and the slurryto form a suspension; and (d) filling a container with the suspension toprepare the single-dose, ready-to-use formulation.
 2. The method ofclaim 1, wherein the aqueous solution comprises a buffer.
 3. The methodof claim 2, wherein the buffer is a phosphate buffer.
 4. The method ofclaim 3, wherein the phosphate buffer is selected from the groupconsisting of sodium phosphate dibasic, sodium phosphate monobasic,potassium phosphate monobasic, potassium phosphate dibasic, and mixturesthereof.
 5. The method of claim 4, wherein the phosphate buffer is amixture of sodium phosphate dibasic heptahydrate and sodium phosphatemonobasic monohydrate.
 6. The method of claim 3, wherein the buffer isphosphate buffered saline.
 7. The method of claim 1, wherein the aqueoussolution comprises an excipient.
 8. The method of claim 7, wherein theexcipient comprises a surfactant, a viscosity enhancer, or a mixturethereof.
 9. The method of claim 8, wherein the viscosity enhancer is awater-soluble cellulose derivative.
 10. The method of claim 9, whereinthe cellulose derivative is sodium carboxymethylcellulose.
 11. Themethod of claim 8, wherein the surfactant is a polysorbate.
 12. Themethod of claim 8, wherein the aqueous solution comprises about 0.01g/kg to about 50 g/kg; about 1.0 g/kg to about 50 g/kg; about 1 g/kg toabout 25 g/kg; about 1 g/kg to about 10 g/kg; about 1 g/kg to about 7.5g/kg; about 1 g/kg to about 5.5 g/kg; about 1 g/kg to about 2.5 g/kg;about 2.5 g/kg to about 50 g/kg; about 5 g/kg to about 50 g/kg; about 10g/kg to about 50 g/kg; about 25 g/kg to about 50 g/kg; about 2.5 g/kg toabout 7.5 g/kg; about 5 g/kg to about 10 g/kg; or about 10 g/kg to about20 g/kg of the viscosity enhancer.
 13. The method of claim 12, whereinthe aqueous solution comprises about 5.5 g/kg of the viscosity enhancer.14. The method of claim 8, wherein the aqueous solution comprises about0.01 g/kg to about 5 g/kg; about 0.01 g/kg to about 2.5 g/kg; about 0.01g/kg to about 1 g/kg; about 0.01 g/kg to about 0.75 g/kg; about 0.01g/kg to about 0.5 g/kg; about 0.01 g/kg to about 0.25 g/kg; about 0.025g/kg to about 5 g/kg; about 0.05 g/kg to about 5 g/kg; about 1 g/kg toabout 5 g/kg; about 0.1 g/kg to about 5 g/kg; 0.1 g/kg to about 2.5g/kg; about 0.1 g/kg to about 1 g/kg; about 0.1 g/kg to about 0.75 g/kg;about 0.1 g/kg to about 0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg;about 0.25 g/kg to about 5 g/kg; about 0.5 g/kg to about 5 g/kg; about 1g/kg to about 5 g/kg; about 2.5 g/kg to about 5 g/kg; about 0.25 g/kg toabout 0.75 g/kg; about 0.5 g/kg to about 1 g/kg; or about 1 g/kg toabout 2 g/kg of the surfactant.
 15. The method of claim 14, wherein theaqueous solution comprises about 0.5 g/kg of the surfactant.
 16. Themethod of claim 8, wherein the aqueous solution comprises about 5.5 g/kgof sodium carboxymethylcellulose and about 0.5 g/kg of polysorbate 80.17. The method of claim 1, wherein the slurry comprises about 0.001 g/kgto about 5 g/kg; about 0.001 g/kg to about 2.5 g/kg; about 0.001 g/kg toabout 1 g/kg; about 0.001 g/kg to about 0.75 g/kg; about 0.001 g/kg toabout 0.5 g/kg; about 0.001 g/kg to about 0.25 g/kg; about 0.001 g/kg toabout 0.01 g/kg; about 0.01 g/kg to about 5 g/kg; about 0.01 g/kg toabout 2.5 g/kg; about 0.01 g/kg to about 1 g/kg; about 0.01 g/kg toabout 0.75 g/kg; about 0.01 g/kg to about 0.5 g/kg; about 0.01 g/kg toabout 0.25 g/kg; about 0.1 g/kg to about 2.5 g/kg; about 0.1 g/kg toabout 1 g/kg; about 0.1 g/kg to about 0.75 g/kg; about 0.1 g/kg to about0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg; about 0.25 g/kg to about 5g/kg; about 0.5 g/kg to about 5 g/kg; about 1 g/kg to about 5 g/kg;about 2.5 g/kg to about 5 g/kg; about 0.25 g/kg to about 0.75 g/kg;about 0.5 g/kg to about 1 g/kg; or about 1 g/kg to about 2 g/kg of thecompound of Formula (I).
 18. The method of claim 17, wherein the slurrycomprises about 0.15 g/kg, about 0.35 g/kg, or about 1.15 g/kg of thecompound of Formula (I).
 19. The method of claim 1, wherein the compoundof Formula (I) comprises no more than about 1% by weight of polymorphForm
 9. 20. The method of claim 1, wherein the compound of Formula (I)comprises less than about 0.1% by weight of polymorph Form
 9. 21. Themethod of claim 1, wherein the slurry comprises an excipient.
 22. Themethod of claim 21, wherein the excipient comprises a surfactant. 23.The method of claim 22, wherein the surfactant is a polysorbate.
 24. Themethod of claim 23, wherein the slurry comprises about 0.15 g/kg of thecompound of Formula (I) and about 0.5 g/kg of polysorbate
 80. 25. Themethod of claim 23, wherein the slurry comprises about 0.35 g/kg of thecompound of Formula (I) and about 0.5 g/kg of polysorbate
 80. 26. Themethod of claim 23, wherein the slurry comprises about 1.15 g/kg of thecompound of Formula (I) and about 0.5 g/kg of polysorbate
 80. 27. Themethod of claim 22, wherein the slurry comprises about 0.01 g/kg toabout 5 g/kg; 0.01 g/kg to about 2.5 g/kg; about 0.01 g/kg to about 1g/kg; about 0.01 g/kg to about 0.75 g/kg; about 0.01 g/kg to about 0.5g/kg; about 0.01 g/kg to about 0.25 g/kg; about 0.025 g/kg to about 5g/kg; about 0.05 g/kg to about 5 g/kg; about 1 g/kg to about 5 g/kg;about 0.1 g/kg to about 5 g/kg; 0.1 g/kg to about 2.5 g/kg; about 0.1g/kg to about 1 g/kg; about 0.1 g/kg to about 0.75 g/kg; about 0.1 g/kgto about 0.5 g/kg; about 0.1 g/kg to about 0.25 g/kg; about 0.25 g/kg toabout 5 g/kg; about 0.25 g/kg to about 2.5 g/kg; about 0.25 g/kg toabout 0.75 g/kg; about 0.5 g/kg to about 5 g/kg; about 0.5 g/kg to about2.5 g/kg; about 0.5 g/kg to about 1 g/kg; about 1 g/kg to about 5 g/kg;about 2.5 g/kg to about 5 g/kg; or about 1 g/kg to about 2 g/kg of thesurfactant.
 28. The method of claim 27, wherein the slurry comprisesabout 0.5 g/kg of the surfactant.
 29. The method of claim 1, wherein theaqueous solution is a filtered mixture.
 30. The method of claim 1,wherein the aqueous solution comprises a sterile diluent.
 31. The methodof claim 1, wherein the aqueous solution is a first sterilized mixture;the slurry is a second sterilized mixture; and the process comprisesmixing the first sterilized mixture and the second sterilized mixture.32. The method of claim 1, wherein the aqueous solution and the slurryare mixed to form a suspension comprising about 0.005 mg/mL to about 2.5mg/mL, about 0.01 mg/mL to about 2.0 mg/mL, about 0.01 mg/mL to about 1mg/mL, about 0.01 mg/mL to about 0.5 mg/mL, about 0.01 mg/mL to about0.2 mg/mL, or about 0.015 mg/mL to about 0.115 mg/mL of the compound ofFormula (I).
 33. The method of claim 1, wherein the container comprisesa suspension comprising about 0.005 mg/mL to about 2.5 mg/mL, about0.005 mg/mL to about 2 mg/mL, about 0.001 mg/mL to about 2 mg/mL, about0.01 mg/mL to about 1.8 mg/mL, about 0.015 mg/mL to about 0.115, about0.025 mg/mL to about 1.6 mg/mL, about 0.05 mg/mL to about 1.5 mg/mL,about 0.075 mg/mL to about 1.25 mg/mL, about 0.1 mg/mL to about 1 mg/mL,or about 0.25 mg/mL to about 0.75 mg/mL of the compound of Formula (I).34. The method of claim 1, wherein the container is selected from thegroup consisting of a vial, a bottle, an ampule, and a syringe.
 35. Themethod of claim 34, wherein the vial is a glass vial, or a plastic vialmade of polyethylene, polypropylene, polyolefins, polyethyleneterephthalate, polyethylene terephthalate G, poly(vinyl chloride), andmixtures thereof.
 36. The method of claim 1, wherein the container has avolume of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10mL.
 37. The method of claim 36, wherein the container is a 3 mLpolypropylene vial.
 38. The method of claim 36, wherein the container isa 2 mL glass vial.
 39. The method of claim 1, wherein the mixing is doneaseptically.
 40. The method of claim 1, wherein the filling is doneaseptically.
 41. The method of claim 1, wherein the filled container isterminally sterilized.
 42. The method of claim 1, wherein theadministration is intra-articular.
 43. The method of claim 42, whereinthe formulation is administered once.
 44. The method of claim 42,wherein the formulation is administered more than once with eachinjection separated by about 3 months to about 60 months.
 45. The methodof claim 44, wherein the formulation is administered once monthly, every3 months, every 6 months, or every 60 months.